WO2020148317A1 - Composés hybrides de peptide-oligourée - Google Patents

Composés hybrides de peptide-oligourée Download PDF

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Publication number
WO2020148317A1
WO2020148317A1 PCT/EP2020/050880 EP2020050880W WO2020148317A1 WO 2020148317 A1 WO2020148317 A1 WO 2020148317A1 EP 2020050880 W EP2020050880 W EP 2020050880W WO 2020148317 A1 WO2020148317 A1 WO 2020148317A1
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Prior art keywords
peptide
oligourea
hybrid
glp
disease
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PCT/EP2020/050880
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English (en)
Inventor
Robert Zimmer
Gilles Guichard
Sebastien Goudreau
Claire Venin
Laura Mauran
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Ureka Sarl
Centre National De La Recherche Scientifique (Cnrs)
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Priority to EP20700893.9A priority Critical patent/EP3911960A1/fr
Publication of WO2020148317A1 publication Critical patent/WO2020148317A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/74—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving hormones or other non-cytokine intercellular protein regulatory factors such as growth factors, including receptors to hormones and growth factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present description relates to peptidomimetic foldamers, and their synthesis.
  • the description provides peptide-amino urea hybrid peptidomimetic foldamers comprising an alpha amino acid peptide portion and an oligourea portion.
  • Proteins and peptides are capable of adopting compact, well-ordered conformations, and performing complex chemical operations, e.g., catalysis, highly selective recognition, etc.
  • the three dimensional structure is the principal determinant that governs specificity in protein-protein and/or protein-substrate interactions.
  • the conformation of peptides and proteins is central for their biological function, pharmaceutical efficacy, and their therapeutic preparation.
  • R&D pharmaceutical research and development
  • peptides have proved to be valuable tools to access extra-cellular targets with medium to large active sites and they are now intensively investigated to access intracellular protein-protein interaction (PPI) targets, a very important topic in recent pharmaceutical research. This is remarkable considering peptides have important shortcomings as they generally show poor membrane permeability, poor bioavailability, and short in vivo half-life.
  • PPI protein-protein interaction
  • Protein folding is inextricably linked to function in both proteins and peptides because the creation of an "active site" requires proper positioning of reactive groups.
  • Much effort has been invested in peptide and peptidomimetic chemistries to address those weaknesses in the hope of finding an alternative to peptides.
  • Researches have endeavoured to identify synthetic polymer or oligomers, which display discrete and predictable (i.e., stable) folding and oligomerizing propensities (hereinafter referred to as "foldamers”) to mimic natural biological systems.
  • Foldamers are also interesting molecules because of their conformational behavior.
  • the elucidation of foldamers having discrete conformational propensities akin to those of natural proteins has led to explorations of peptides constructed from b-, g-, or d-amino acids.
  • Both the 314 and 2.512 helical backbones have been found suitable for the design of stabilized helical peptides useful for therapeutic purposes.
  • amphiphilic 314-helical b-peptides have been constructed from hydrophobic-cationic-hydrophobic- or hydrophobic-hydrophobic-cationic residue triads.
  • a key principle of foldamer research is to use biomolecules as inspiration for the design and development of molecules with functions and capabilities beyond those found in nature, such as catalysts or artificial bio-receptors with tailored ligand specificity.
  • As function is intimately linked with structure the creation of new and unique foldamer architectures is a necessary step towards the goal of developing foldamers with tailored/preternatural functions.
  • the construction of novel foldamer structures can be challenging, particularly the creation of multi-component architectures, which require controlled, precise self-assembly.
  • oligoureas comprising amino acid side chains or analogs thereof are in the limited list of such potential foldamers as they offer 3-D space similarity, metabolic compatibility, water solubility, and flexibility of functionalities.
  • oligoureas alkylene diamine residues having a urea bridging unit
  • oligoureas are synthesised by iterative coupling on solid support and possess their own secondary, tertiary and quaternary structures based on their sequences.
  • the compatibility of peptide-oligourea hybrids in biological systems and their utilisation in vivo is not well understood.
  • the oligourea backbone is resistant to proteases and can be interfaced with peptide a-helices as it adopts an helical conformation that does not disrupt the peptide a-helix propagation.
  • This is noteworthy as 1) many biologically active peptides contain an a-helix (a large fraction of PPIs involve an a-helix) and 2) those portions could potentially be replaced or partially replaced by oligoureas to preserve binding while improving the proteolytic resistance of the peptide.
  • Such strategy would be a valuable tool to design new peptide therapeutics as their pharmaceutical properties could be improved.
  • Oligoureas represent interesting classes of peptidomimetic foldamers that have previously received little attention.
  • the present disclosure relates to the surprising and unexpected discovery that alpha-amino acid peptide-amino urea hybrid foldamer compounds (i.e., “peptide-amino urea hybrids” or“peptide-oligourea hybrids”) can be designed, which preserve the function of the native or parental alpha-amino acid peptide, but that also demonstrate superior half-life and protease resistance.
  • the peptide-oligourea hybrids as described herein are compounds in which a portion of the native or parental alpha-amino acid sequence is replaced or substituted by at least one amino urea residue comprising substitutions, e.g., naturally or non-naturally occurring amino acid side chains, that mimic the secondary structure conformation and biochemistry of the native or parental peptide (a substitution comprising a plurality of amino urea residues is referred to herein as an“oligourea”).
  • substitutions e.g., naturally or non-naturally occurring amino acid side chains
  • the peptide-oligourea hybrid compounds as described herein can adopt desired secondary structures similar to the native or parental peptides, including, e.g., helicoidal structures, they can serve as, for example, receptor ligands, effector molecules, agonists, antagonists, modulators of protein-protein interactions, organocatalysts, or enzymes.
  • the description provides a compound of the structure:
  • Y and Z represent alpha-amino acid residues of a native or parent peptide; each n is independently an integer > 1 ; X 11 represents a non-peptide amino urea or ureido residue substitution of two or more alpha-amino acids of the native or parent peptide; and m is an integer > 1, wherein the non-peptide amino urea residue substitution is configured to mimic the native or parent alpha-amino acid side-chain chemistry and/or 3-D configuration, and wherein the peptide-amino urea hybrid compound retains at least one of binding activity, biological activity or both of the native or parent peptide.
  • each n is independently an integer greater than or equal to two. In some embodiments, n is an integer from 2-50. In certain embodiments, m is an integer greater than or equal to 1. In some embodiments, m is an integer from 1-50. In still further embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  • X u is an optionally substituted 1,2-ethylene diamine residue including a urea linking unit such as an N-linked 2- aminoethyl carbamamoyl or 2-aminoethyl urea residue. In certain embodiments, the X u residue includes a substitution with a proteinaceous amino acid side chain at the a-carbon (X ua ), the b- carbon or both.
  • the peptide-amino urea hybrid compounds comprise a substitution comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more non-peptide amino urea or ureido peptidomimetic residues. That is, the native or parent peptide includes a substitution of alpha-amino acids with non-peptide amino urea or ureido peptidomimetic residues.
  • the hybrid compounds described herein comprise amino urea residues of formula I:
  • R a , R R and R”’ a groups are independently selected from hydrogen, any side chain of a natural amino acid, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic aryl-Cl-C6-alkyl, alkenyl or alkynyl; C1-C6- alkyloxy, aryloxy, heteroaryloxy, thio, Cl-C6-alkylthio, amino, mono ordi-Cl-C6-alkylamino, carboxylic acid, carboxamide mono- or di-Cl-C6-alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, or guanidine.
  • the peptide-amino urea hybrid compounds comprise a substitution comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more non-peptide amino urea or ureido peptidomimetic residues.
  • the hybrid compounds described herein comprise amino urea residues of formula P: wherein R is independently selected from a hydrogen atom, an amino acid side chain, a (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C5-C12) monocyclic or bicyclic aryl, (C5-C14) monocyclic or bicyclic aralkyl, (C5-C14) monocyclic or bicyclic heteroalkyl and (Cl -CIO) monocyclic or bicyclic heteroaryl group comprising up to 5 heteroatoms selected from N, O, and S, said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NC , OH, amidine, benzamidine, imidazole, alkoxy, (C1-C4) alkyl, NH2, CN, trihalomethyl,
  • peptide-amino urea hybrid compounds as described herein comprise amino urea substitutions of a native or parent peptide that is a naturally occurring peptide or a peptide derived from a naturally occurring protein.
  • the parent peptide is a non-naturally occurring peptide or peptidomimetic.
  • the parent peptide is glucagon-like peptide-1 (GLP-1).
  • the peptide-oligourea hybrid compound comprises a substitution of 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more alpha- amino acids of the parent peptide with one or more amino urea residues as described herein.
  • the number of non-peptide oligourea residues is less than the number of alpha-amino acids substituted (i.e., the number of alph-amino acids removed or replaced).
  • the oligourea residues in the substitution comprise proteinaceous side-chains.
  • the peptide-oligourea hybrid compound comprises a number of amino urea residues that is at least one less than the number of alph-amino acids being substituted.
  • the description provides a glucagon-like peptide- 1 (GLP-1)
  • the GLP-1 peptide- oligourea hybrid demonstrates a resistance to dipeptidyl peptidase-4 (DPP-4) in PBS or in serum that is greater than native or naturally occurring GLP-1.
  • the GLP-1 peptide-oligourea hybrid demonstrates a resistance to neutral endopeptidase 24.11 (NEP 24.11) in PBS or in serum that is greater than native or naturally occurring GLP-1.
  • the GLP-1 peptide-oligourea hybrid demonstrates an EC50 of less than about 10 mM.
  • the GLP-1 peptide-oligourea hybrid demonstrates binding to GLP-1 receptor (GLP-1R). In certain embodiments, the GLP-1 peptide-oligourea hybrid demonstrates bioactivity in a cAMP production assay.
  • the peptide-oligourea hybrid has a structure selected from the group of SEQ ID NO. 2-24. In certain embodiments, the peptide-oligourea hybrid as a structures selected from SEQ ID NO. 5, 9, 11, 14, 16, 22, 23, or 24.
  • the description provides a pharmaceutical composition comprising a peptide-oligourea hybrid as described herein, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a peptide-oligourea hybrid as described herein.
  • the effective amount is a therapeutically effective amount or a synergistically effective amount.
  • the description provides a method of treating a disease, comprising administering to a subject in need thereof a composition comprising an effective amount of a peptide-oligourea hybrid as described herein, or a pharmaceutical formulation comprising the same and a pharmaceutically acceptable excipient, wherein composition is effective at treating or ameliorating at least one symptom of the disease.
  • the disease is a metabolic disorder.
  • the disease is diabetes.
  • the oligourea residues are coupled, joined to or contiguous with a peptide a-helix region.
  • the hybrid compounds also comprise amino urea residues are“fused” to a terminus, e.g., amino terminus, carboxy terminus or both, of an a-amino acid peptide.
  • the peptide- oligourea hybrid compounds comprise additional amino urea residues coupled to a side-chain group of a backbone residue (either an alpha amino acid, an amino urea or both).
  • the compounds can further comprise at least one additional chemical modification.
  • the chemical modification includes at least one of, for example, acetylation, phosphorylation, methylation, glycosylation, prenylation, isoprenylation, farnesylation, geranylation, pegylation, a disulfide bond, or combination thereof.
  • the description provides pharmaceutically acceptable acid and base salt forms of the compounds described herein.
  • the oligourea foldamers and compounds as described herein, including pharmaceutically acceptable salts thereof, are useful for the preparation of a medicament and/or the treatment of disease in a subject.
  • the compounds of the disclosure may optionally be administered with at least one of a pharmaceutically acceptable excipient, pharmacologically active agent or a combination thereof.
  • a pharmaceutically acceptable excipient pharmacologically active agent or a combination thereof.
  • compositions comprising an effective amount of a peptide-oligourea hybrid or oligourea foldamers, or a oligourea helical bundle as described herein, and a pharmaceutically acceptable carrier or excipient.
  • the description also provides methods of treating a disease or disorder or ameliorating the effects of the same comprising the steps of administering to an individual in need thereof, a composition comprising: an effective amount of a peptide-oligourea hybrid, oligourea foldamers, a oligourea compound, or salt form thereof as described herein, wherein the composition is effective for treating, preventing or ameliorating the effects of the disease or disorder.
  • the present description provides methods of making and using the compounds, or the compositions as described herein.
  • the oligourea compounds or oligourea foldamers as described herein can be used as a diagnostic agent or a therapeutic agent for the treatment of a disease or condition.
  • the present description provides methods of making oligourea compounds, oligourea foldamer compounds, or peptide-oligourea compounds as described herein.
  • the present description provides for the synthesis of a non peptide helical structure.
  • the present description provides methods of making and using the compounds of the disclosure.
  • the peptide-oligourea hybrid compound is selected from the group consisting of SEQ ID NOs. 2-24.
  • the c-terminus is amidated.
  • the preceding general areas of utility are given by way of example only and are not intended to be limiting on the scope of the present disclosure and appended claims. Additional objects and advantages associated with the compositions, methods, and processes of the present disclosure will be appreciated by one of ordinary skill in the art in light of the instant claims, description, and examples. For example, the various aspects and embodiments of the disclosure may be utilized in numerous combinations, all of which are expressly contemplated by the present description. These additional advantages objects and embodiments are expressly included within the scope of the present disclosure.
  • the publications and other materials used herein to illuminate the background of the disclosure, and in particular cases, to provide additional details respecting the practice, are incorporated by reference, and for convenience are listed in the appended bibliography.
  • the patent or application file contains at least one drawing executed in color.
  • Figure 1 Schematic representation of different GLP-1 analogues previously reported and of the present approach based on peptide/oligourea hybrids.
  • Figures 2A, 2B, and 2C Comparison of a-helical and oligourea backbones.
  • FIGs 4A, 4B, and 4C Blood glucose study in mice.
  • IPGTT Intra peritoneal glucose tolerance test (IPGTT) at different time after dosing in fasted normal mice (C57BL/6J, male, 20-25 g). Dosage: 200 pg/kg ( ⁇ 50 nmol/kg) i.v. Formulation: 20 pg/mL in PBS IX. IPGTT: glucose 2g/kg i.p. at TO, and different time points after dosing.
  • Figure 9 Demonstrattes the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea SEQ ID NO. 3 in cells expressing the GLP-1 R.
  • Figure 10. Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea SEQ ID NO. 4 in cells expressing the GLP-1 R.
  • Figures 11A, 11B, and 11C. (11A) demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea SEQ ID NO. 5 in cells expressing the GLP-1R.
  • (11B) demonstrate the enzymatic degradation of peptide- oligourea hybrid SEQ ID NO. 5 by NEP 24.11.
  • (11C) demonstrates the mouse plasma degradation of peptide-oligourea hybrid SEQ ID NO. 5.
  • Figure 12. Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea SEQ ID NO. 6 in cells expressing the GLP-1R.
  • Figure 13 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 7 in cells expressing the GLP-1R.
  • Figure 14 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 8 in cells expressing the GLP-1R.
  • Figures 15A, 15B, and 15C demonstrate the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea SEQ ID NO. 9 in cells expressing the GLP-1R.
  • (15B) demonstrate the enzymatic degradation of peptide- oligourea hybrid SEQ ID NO. 9 by NEP 24.11.
  • (15C) demonstrates the mouse plasma degradation of peptide-oligourea hybrid SEQ ID NO. 9.
  • Figure 16 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 10 in cells expressing the GLP-1R.
  • FIG. 17A Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 11 in cells expressing the GLP-IR.
  • (17B) demonstrates the enzymatic degradation of peptide-oligourea hybrid SEQ ID NO. 11 by NEP 24.11.
  • (17C) demonrates the mouse plasma degradation of peptide-oligourea hybrid SEQ ID NO. 11.
  • Figure 18 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO 12 in cells expressing the GLP-IR.
  • Figure 19 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 13 in cells expressing the GLP-1R.
  • Figures 20A, 20B, and 20C Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 14 in cells expressing the GLP-1R.
  • (20B) demonstrates the enzymatic degradation of peptide-oligourea SEQ ID NO. 14 by NEP 24.11.
  • (20C) demonstrates the mouse plasma degradation of peptide-oligourea hybrid SEQ ID NO. 14.
  • Figure 21 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 15 in cells expressing the GLP-1R.
  • FIG. 22A Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea SEQ ID NO. 16 in cells expressing the GLP-IR.
  • 22B demonstrates the enzymatic degradation of peptide-oligourea hybrid SEQ ID NO. 16 by NEP 24.11.
  • 22C demonsrates the mouse plasma degradation of peptide-oligourea SEQ ID NO. 16.
  • Figure 23 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 17 in cells expressing the GLP-IR.
  • Figure 24 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 18 in cells expressing the GLP-IR.
  • Figure 25 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 19 in cells expressing the GLP-IR.
  • Figure 26 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination peptide-oligourea hybrid SEQ ID NO. 20 in cells expressing the GLP-IR.
  • Figure 27 Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 21 in cells expressing the GLP-IR.
  • Figures 28A, 28B, and 28C Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea SEQ ID NO. 22 in cells expressing the GLP-1R.
  • 28B demonstrates the enzymatic degradation of peptide-oligourea hybrid SEQ ID NO. 2223 by NEP 24.11.
  • 28C demonstrates the muse plasma degradation of peptide-oligourea hybrid SEQ ID NO. 22.
  • FIG. 29A Demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 23 in cells expressing the GLP-1R.
  • 29B demonstrates the enzymatic degradation of peptide-oligourea hybrid SEQ ID NO. 23 by NEP 24.11.
  • 29C demonstrates the mouse plasma degradation of peptide-oligourea hybrid SEQ ID NO. 23.
  • Figures 30A, 30B, and 30C demonstrate the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid SEQ ID NO. 24 in cells expressing the GLP-1R.
  • (30B) demonstrates the enzymatic degradation of peptide-oligourea hybrid SEQ ID NO. 24 by Pancreatin.
  • (30C) demonstrates the mouse plasma degradation of peptide-oligourea hybrid SEQ ID NO. 24.
  • Figure 32 Demonstrates the enzymatic degradation by NEP 24.11 of the respective peptides (SEQ ID Nos. 2, 3, 6, 10, 12, 15, 17, 23, and 24). (two-way anova and Bonferroni post test: *p ⁇ 0.05; ** p ⁇ 0,01; *** p ⁇ 0,001).
  • Figure 34 Demonstrates the mouse plasma degradation assay (two-way anova and Bonferroni post test: *p ⁇ 0.05; ** p ⁇ 0,01; *** p ⁇ 0,001); (B) Half life in pancreatin (two-way anova and Dunnett post test: *p ⁇ 0.05; ** p ⁇ 0,01 ; *** p ⁇ 0,001); (C) EC50 values and standard error of the mean values.
  • Figure 35 Demonstrates the enzymatic degradation (Pancreatin) (two-way anova and Bonferroni post test: *p ⁇ 0.05; ** p ⁇ 0,01; *** p ⁇ 0,001) (A); (B) Half life in pancreatin (two- way anova and Dunnett post test: *p ⁇ 0.05; ** p ⁇ 0,01; *** p ⁇ 0,001); (C) EC50 values and standard error of the mean values.
  • Figure 36 Demonstrates the fasting blood glucose (mg/dL) before and after i.v treatment in mice treated with vehicle, 1, 14, 22, 23, 5 pg/mouse (two-way ANOVA and Bonferroni post-test: ** p ⁇ 0,01 ; *** p ⁇ 0,001).
  • Figures 37A and 37B Demonstrates the concentration-response curve (receptor- mediated cAMP produced) for EC50 determination of oligomer 24 and 25 in cells expressing the GLP-1R (37A).
  • 37B EC50 values and standard error of the mean values.
  • 38B AUC of the IPGTT curves.
  • 38C Pancreatin degradation assay (two-way anova and Bonferroni post test: * p ⁇ 0.05; ** p ⁇ 0,01; *** p ⁇ 0,001 ; one way anova with Dunnett’s multiple comparison test: # p ⁇ 0,05; ### p ⁇ 0,001 )
  • oligoureas represent interesting classes of peptidomimetic foldamers.
  • alpha-amino acid peptide-amino urea hybrid foldamer compounds i.e.,“peptide-amino urea hybrid” or“peptide-oligourea hybrid” compounds
  • “peptide-amino urea hybrid” or“peptide-oligourea hybrid” compounds that preserve the function of the native or parental alpha-amino acid peptide, but that also demonstrate superior half-life and protease resistance.
  • the peptide-oligourea hybrid compounds as described herein are compounds in which a portion of the native or parental alpha-amino acid sequence is replaced or substituted by at least one amino urea residue comprising substitutions, e.g., naturally or non-naturally occurring amino acid side chains, that mimic the secondary structure conformation and biochemistry of the native or parental peptide (a substitution comprising a plurality of amino urea residues is referred to herein as an“oligourea”).
  • substitutions e.g., naturally or non-naturally occurring amino acid side chains
  • the peptide-oligourea hybrid compounds as described herein can adopt desired secondary structures similar to the native or parental peptides, including, e.g., helicoidal structures, they can serve as, for example, receptor ligands, effector molecules, agonists, antagonists, modulators of protein- protein interactions, organocatalysts, or enzymes.
  • a reference to "A and/or B", when used in conjunction with open-ended language such as “comprising” can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); etc.
  • the phrase "at least one,” in reference to a list of one or more elements, should be understood to mean at least one element selected from anyone or more of the elements in the list of elements, but not necessarily including at least one of each and every element specifically listed within the list of elements and not excluding any combinations of elements in the list of elements.
  • This definition also allows that elements may optionally be present other than the elements specifically identified within the list of elements to which the phrase "at least one" refers, whether related or unrelated to those elements specifically identified.
  • At least one of A and B can refer, in one embodiment, to at least one, optionally including more than one, A, with no B present (and optionally including elements other than B); in another embodiment, to at least one, optionally including more than one, B, with no A present (and optionally including elements other than A); in yet another embodiment, to at least one, optionally including more than one, A, and at least one, optionally including more than one, B (and optionally including other elements); etc.
  • “Peptides” are typically short chains of amino acid monomers linked by peptide
  • (amide) bonds the covalent chemical bonds formed when the carboxyl group of one amino acid reacts with the amino group of another.
  • the shortest peptides are dipeptides, consisting of 2 amino acids joined by a single peptide bond, followed by tripeptides, tetrapeptides, etc.
  • a polypeptide is a long, continuous, and unbranched peptide chain.
  • amino refers to -NH2 and substituted derivatives thereof wherein one or both of the hydrogens are independently replaced with 20 substituents selected from the group consisting of alkyl, haloalkyl, fluoro alkyl , alkenyl, alkynyl, carbocyclyl, heterocyclyl, aryl, aralkyl, hetero aryl , hetero aralkyl , alkylcarbonyl, haloalkylcarbonyl, carbocyclylcarbonyl, fluoroalkylcarbonyl, alkenylcarbonyl, heterocyclylcarbonyl, arylcarbonyl, alkynylcarbonyl, aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl and the sulfonyl and sulfinyl groups defined above; or when both hydrogens together are replaced with an alkylene group (to form a ring
  • amino acid refers to any molecule that contains both amino and carboxylic acid functional groups, and includes any of the naturally occurring amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, Hyl, Hyp, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D, L, or DL form.
  • naturally occurring amino acids e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, Hyl, Hyp, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val
  • side chains of naturally occurring amino acids include, for example, hydrogen (e.g., as in glycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., as in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine), alkaryl (e.g., as in phenylalanine and tryptophan), substituted arylalkyl (e.g., as in tyrosine), and heteroarylalkyl
  • hydrogen e.g., as in glycine
  • alkyl e.g., as in alanine, valine, leucine, isoleucine, proline
  • substituted alkyl e.g., as in threonine, serine, methionine, cysteine, aspartic
  • amino acid sidechain or“amino acid residue” shall mean, within context, a radical of a D- or L-amino acid sidechain (derived from an amino acid) which functions as a substituent on another group, often an alkylene (usually a methylene) group on R2’ or R3’ as otherwise described herein.
  • Preferred amino acid sidechains for use in the present disclosure are derived from the sidechains of both natural and unnatural amino acids, preferably including, for example, alanine, b-alanine, arginine, asparagine, aspartic acid, cyclohexylalanine, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, naphthylalanine, norleucine, norvaline, proline, serine, threonine, valine, tryptophan or tyrosine, among others.
  • any amino acid can mean any natural or synthetic amino acid, including a-, b-, g-, or d-amino acids, possibly modified by the presence of one or more substituents, or combinations thereof, including analogs, derivatives, mimetics, and peptoid versions of the same. More precisely the term a- amino acid means an alpha aminated amino acid with the following general structure: COOH
  • R represents the side chain of the amino acid.
  • R therefore represents the side chain of a side or non-side amino acid.
  • the term “natural amino acid” means any amino acid which is found naturally in vivo in a living being. Natural amino acids therefore include amino acids coded by mRNA incorporated into proteins during translation but also other amino acids found naturally in vivo which are a product or by product of a metabolic process, such as for example ornithine which is generated by the urea production process by arginase from L-arginine. In the present disclosure, the amino acids used can therefore be natural or not. Namely, natural amino acids generally have the L configuration but also, according to the disclosure, an amino acid can have the L or D configuration. Moreover, R is of course not limited to the side chains of natural amino acid but can be freely chosen.
  • a“urea” group is an organic compound with the chemical formula
  • Oligomers of, e.g., ethylenediamine residues having a urea linkage can be synthesized from ethyldiamine carbamoyl residues.
  • the term“peptide precursor” or“parental peptide” refers, but is in no way limited to, a parental a-peptide sequence that is coupled with oligourea pseudopeptide or peptidomimetic subunits or substituting oligourea pseudopeptide subunits (i.e., exchanging one or more a-amino acids for one or more oligourea pseudopeptide subunits).
  • oligourea refers, but is in no way limited to, a residue containing N, N’ -linked urea residues including oligomers of substituted or unsubstituted N-2-ethylaminocarbamoyl or 1, 2-ethylene diamine residues.
  • compound refers to any specific chemical compound disclosed herein and includes tautomers, regioisomers, geometric isomers, and where applicable, stereoisomers, including optical isomers (enantiomers) and other steroisomers (diastereomers) thereof, as well as pharmaceutically acceptable salts and derivatives (including prodrug forms) thereof where applicable, in context.
  • compound generally refers to a single compound, but also may include other compounds such as stereoisomers, regioisomers and/or optical isomers (including racemic mixtures) as well as specific enantiomers or enantiomerically enriched mixtures of disclosed compounds.
  • the term also refers, in context to prodrug forms of compounds which have been modified to facilitate the administration and delivery of compounds to a site of activity. It is noted that in describing the present compounds, numerous substituents and variables associated with same, among others, are described. It is understood by those of ordinary skill that molecules which are described herein are stable compounds as generally described hereunder. When the bond is shown, both a double bond and single bond are represented within the context of the compound shown.
  • hydrocarbyl shall mean a compound which contains carbon and hydrogen and which may be fully saturated, partially unsaturated or aromatic and includes aryl groups, alkyl groups, alkenyl groups and alkynyl groups.
  • amido as used herein means an ammo group, as defined herein, appended to the parent molecular moiety through a carbonyl.
  • nitro as used herein means a -N02 group.
  • zido as used herein means a -N3 group.
  • Me, Et, Ph, Tf, Nf, Ts, Ms, Cbz, and Boc represent methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl, methanesulfonyl, carbobenzyloxy, and tert-butyloxycarbonyl, respectively.
  • Alkyl refers to a branched or unbranched alkyl group having 1-6 carbon atoms, a branched or unbranched alkenyl group having 1-6 carbon atoms, a branched or unbranched alkinyl group having 1-6 carbon atoms.
  • alkyl shall mean within its context a linear, branch-chained or cyclic fully saturated hydrocarbon radical or alkyl group, preferably a Cl- C10, more preferably a C1-C6, alternatively a C1-C3 alkyl group, which may be optionally substituted.
  • alkyl groups are methyl, ethyl, n-butyl, sec-butyl, n-hexyl, n-heptyl, n- octyl, n-nonyl, n-decyl, isopropyl, 2-methylpropyl, cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl, cyclopentylethyl, cyclohexylethyl and cyclohexyl, among others.
  • compounds according to the present disclosure which may be used to covalently bind to dehalogenase enzymes.
  • These compounds generally contain a side chain (often linked through a polyethylene glycol group) which terminates in an alkyl group which has a halogen substituent (often chlorine or bromine) on its distil end which results in covalent binding of the compound containing such a moiety to the protein.
  • a side chain often linked through a polyethylene glycol group
  • a halogen substituent often chlorine or bromine
  • alkynyl refers to linear, branchchained or cyclic C2-C10 (preferably C2-C6) hydrocarbon radicals containing at least one CoC bond.
  • alkylene when used, refers to a -(CH2)n- group (n is an integer generally from 0-6), which may be optionally substituted.
  • the alkylene group preferably is substituted on one or more of the methylene groups with a C1-C6 alkyl group (including a cyclopropyl group or a t-butyl group), more preferably a methyl group, but may also be substituted with one or more halo groups, preferably from 1 to 3 halo groups or one or two hydroxyl groups or 0-(Cl-C6 alkyl) groups.
  • an alkylene group may be substituted with a urethane or alkoxy group (or other group) which is further substituted with a polyethylene glycol chain (of from 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units) to which is substituted (preferably, but not exclusively on the distal end of the polyethylene glycol chain) an alkyl chain substituted with a single halogen group, preferably a chlorine group.
  • a polyethylene glycol chain of from 1 to 10, preferably 1 to 6, often 1 to 4 ethylene glycol units
  • the alkylene group may be substituted with an amino acid side chain such as group obtained from an amino acid (a natural or unnatural amino acid) such as, for example, alanine, b-alanine, arginine, asparagine, aspartic acid, cysteine, cystine, glutamic acid, glutamine, glycine, phenylalanine, histidine, isoleucine, lysine, leucine, methionine, proline, serine, threonine, valine, tryptophan or tyrosine.
  • amino acid a natural or unnatural amino acid
  • the term“unsubstituted” shall mean substituted only with hydrogen atoms.
  • a range of carbon atoms which includes CO means that carbon is absent and is replaced with H.
  • a range of carbon atoms which is C0-C6 includes carbons atoms of 1, 2, 3, 4, 5 and 6 and for CO, H stands in place of carbon.
  • substituted or“optionally substituted” shall mean independently (i.e., where more than substituent occurs, each substituent is independent of another substituent), one or more substituents (independently, up to five substitutents, preferably up to three substituents, often 1 or 2 substituents on a moiety in a compound according to the present disclosure and may include substituents which themselves may be further substituted) at a carbon (or nitrogen) position anywhere on a molecule within context, and independently includes as substituents hydroxyl, thiol, carboxyl, cyano (CoN), nitro (N02), halogen (preferably, 1, 2 or 3 halogens, especially on an alkyl, especially a methyl group such as a trifluoromethyl), an alkyl group (preferably, Cl -CIO , more preferably, C1-C6), aryl (especially phenyl and substituted phenyl for example benzyl or benzoyl), alkoxy group (preferably, C
  • substituted (each substituent being independent of another substituent) shall also mean within its context of use C1-C6 alkyl, C1-C6 alkoxy, halogen, amido, carboxamido, sulfone, including sulfonamide, keto, carboxy, C1-C6 ester (oxyester or carbonylester), C1-C6 keto, urethane -0-C(0)-NRlR2 or -N(Rl)-C(0)-0-Rl, nitro, cyano and amine (especially including a C1-C6 alkylene-NRlR2, a mono- or di- C1-C6 alkyl substituted amines which may be optionally substituted with one or two hydroxyl groups).
  • R1 and R2 are each, within context, H or a C1-C6 alkyl group (which may be optionally substituted with one or two hydroxyl groups or up to three halogen groups, preferably fluorine).
  • the term“substituted” shall also mean, within the chemical context of the compound defined and substituent used, an optionally substituted aryl or heteroaryl group or an optionally substituted heterocyclic group as otherwise described herein.
  • Alkylene groups may also be substituted as otherwise disclosed herein, preferably with optionally substituted C1-C6 alkyl groups (methyl, ethyl or hydroxymethyl or hydroxyethyl is preferred, thus providing a chiral center), an amido group as described hereinabove, or a urethane group 0-C(0)-NRlR2 group where R1 and R2 are as otherwise described herein, although numerous other groups may also be used as substituents.
  • Various optionally substituted moieties may be substituted indepencetnly with 3 or more substituents, preferably no more than 3 substituents and preferably with 1 or 2 substituents.
  • Haldroxyl refers the functional group -OH when it is a substituent in an organic compound.
  • Heterocycle refers to a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S, and may be aromatic (heteroaryl) or non-aromatic.
  • heteroaryl moieties are subsumed under the definition of heterocycle, depending on the context of its use. Exemplary heteroaryl groups are described hereinabove.
  • nonaromatic heterocyclic groups for use in the present disclosure include, for example, pyrrolidinyl, pyrrolinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, imidazolinyl, pyrazolidinyl, imidazolidinyl, morpholinyl, tetrahydropyranyl, azetidinyl, oxetanyl, oxathiolanyl, pyridone, 2-pyrrolidone, ethyleneurea, 1,3-dioxolane, 1,3-dioxane, 1,4-dioxane, phthalimide and succinimide, among others.
  • Heterocyclic groups can be optionally substituted with 1 to 5, and preferably 1 to 3 substituents, selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro,— SO-alkyl,— SO-substi
  • nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-
  • Heteroaryl refers to a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S with at least one ring of this group being aromatic. Heteroaryl groups having one or more nitrogen, oxygen, or sulfur atoms in the ring (moncyclic) such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as indole, quinoline, indolizine, azaindolizine, benzofurazan, etc., among others, which may be optionally substituted as described above.
  • monocyclic such as imidazole, furyl, pyrrole, furanyl, thiene, thiazole, pyridine, pyrimidine, pyrazine, triazole, oxazole or fused ring systems such as ind
  • heteroaryl groups include nitrogen containing heteroaryl groups such as pyrrole, pyridine, pyridone, pyridazine, pyrimidine, pyrazine, pyrazole, imidazole, triazole, triazine, tetrazole, indole, isoindole, indolizine, azaindolizine, purine, indazole, quinoline, dihydroquinoline, tetrahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, quinolizine, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, imidazopyridine, imidazotriazine, pyrazinopyridazine, acridine, phenanthridine, carbazole, carbazoline, perimidine, phenanthroline,
  • Substituted heteroaryl refers to a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, O or S with at least one ring of this group being aromatic and this group being substituted with one or more substituents selected from the group consisting of halogen, alkyl, carbyloxy, carbylmercapto, alkylamino, amido, carboxyl, hydroxyl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • thiol refers to the group— SH.
  • thioalkoxy refers to the group— S-alkyl.
  • Alkoxyl refers to an alkyl group linked to oxygen thus: R-0-, where R is an alkyl.
  • Substituted alkyl refers to a branched or unbranched alkyl, alkenyl or alkinyl group having 1-10 carbon atoms and having substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulfo or acyl.
  • substituent generic groups having the meanings being identical with the definitions of the corresponding groups as defined herein.
  • Halogen refers to fluorine, bromine, chlorine, and iodine atoms.
  • Acyl denotes the group— C(0)R e , where R e is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl whereas these generic groups have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • Acloxy denotes the group — OAc, where Ac is an acyl, substituted acyl, heteroacyl or substituted heteroacyl whereas these generic groups have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • Alkylamino denotes the group— NR f R g , where Rr and R g , that are independent of one another, represent hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, whereas these generic substituents have meanings which are identical with definitions of the corresponding groups defined herein.
  • Aryl refers to an aromatic carbocyclic group having from 1 to 18 carbon atoms and being a substituted (as otherwise described herein) or unsubstituted monovalent aromatic radical having a single ring (e.g., benzene, phenyl, benzyl) or condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, anthracenyl, phenanthrenyl, etc.) and can be bound to the compound according to the present disclosure at any available stable position on the ring(s) or as otherwise indicated in the chemical structure presented.
  • Other examples of aryl groups, in context, may include heterocyclic aromatic ring systems.
  • Substituted aryl refers to an aromatic carbocyclic group having from 1 to 18 carbon atoms and being composed of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic.
  • the ring(s) are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxyl, carbylmercapto, alkylamino, carbyloxy, amino, amido, carboxyl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • Carboxyl denotes the group— C(0)OR, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl , whereas these generic substituents have meanings which are identical with definitions of the corresponding groups defined herein.
  • Cycloalkyl refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms.
  • Substituted cycloalkyl refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms and being substituted by one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent groups have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • Heterocycloalkyl refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P.
  • Substituted heterocycloalkyl refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, O, S or P and the group is containing one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend.
  • alkenyl refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms.
  • Imidazole refers to a heterocyclic base of the general formula: C3H4N2.
  • Alkyl group refers to, for example, a Cl -C6 alkyl group which is attached to
  • aromatic hydrocarbon rings having from 6 to 10 carbon atoms and which has a total of 7 to 14 carbon atoms, such as the benzyl, alpha-naphthylmethyl, indenylmethyl, diphenylmethyl, 2- phenethyl, 2-alpha-naphthylethyl, 3-phenylpropyl, 3-alpha-naphthylpropyl, phenylbutyl, 4-alpha- naphthylbutyl or 5-phenylpentyl groups.
  • “Guanidine” refers generally to the amidine of amidocarbonic acid and has the general formula of: C(NH2)3.
  • aralkyl and“heteroarylalkyl” refer to groups that comprise both aryl or, respectively, heteroaryl as well as alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systems according to the above definitions.
  • the description provides for oligourea compounds comprising aliphatic oligoureas at least partially encapsulating an agent.
  • the aliphatic oligoureas form a oligourea helical bundle.
  • the aliphatic oligoureas are comprised of short amphiphilic a-helicomimetic foldamers with proteinaceous sidechains.
  • the short amphiphilic a-helicomimetic foldamers self-assemble into the oligourea helical bundle.
  • the foldamers can self-assemble under aqueous conditions.
  • the compounds as described herein can adopt desired secondary structures similar to native peptides, including, e.g., helicoidal structures, they can serve as, for example, receptor ligands, effector molecules, agonists, antagonists, modulators of protein-protein interactions, organocatalysts, or enzymes.
  • the description provides hybrid compounds comprising amino urea residues or oligomers of the same (i.e., oligoureas).
  • compounds as described herein comprise optionally substituted C1-C4 alkylene diamine residues having a urea bridging unit (e.g., N, N’-linked).
  • the residues are formed from a Cl- C4 diaminoalkyl carbamoyl.
  • the hybrid compounds comprise one or more optionally substitutued 1, 2-ethylene diamine residues having a urea bridging unit, or an optionally substituted l-(2-aminoethyl urea) residue, or 2-aminoethyl cabamoyl residue, wherein substitution is an amino acid side chain.
  • the description provides a compound of the structure:
  • Y and Z represent alpha-amino acid residues of a native or parent peptide; each n is independently an integer > 1 ; X u represents a non-peptide amino urea or ureido residue substitution of two or more alpha-amino acids of the native or parent peptide; and m is an integer > 1, wherein the non-peptide amino urea residue substitution is configured to mimic the native or parent alpha-amino acid side-chain chemistry and/or 3-D configuration, and wherein the peptide-amino urea hybrid compound retains at least one of binding activity, biological activity or both of the native or parent peptide.
  • each n is independently an integer greater than or equal to two. In some embodiments, n is an integer from 2-50. In certain embodiments, m is an integer greater than or equal to 1. In some embodiments, m is an integer from 1-50. In still further embodiments, m is 1, 2, 3, 4, 5, 6, 7, 8, or 9.
  • X u is an optionally substituted 1,2-ethylene diamine residue including a urea linking unit such as an N-linked 2- aminoethyl carbamamoyl or 1 -(2-aminoethyl urea) residue.
  • the X 11 residue includes a substitution with a proteinaceous amino acid side chain at the second, i.e., a- carbon (X uu ), the b-carbon or both.
  • the present description provides peptide-oligourea hybrid foldamer compounds comprising alpha-amino acid residues, and non-peptide oligourea residues.
  • the non-peptide oligourea residues form a helix.
  • the non-peptide oligourea helical foldamer is an aliphatic oligourea.
  • the non-peptide oligourea helical foldamer is a short amphiphilic a-helicomimetic foldamer with proteinaceous side-chains.
  • the peptide-oligourea hybrid compounds comprise a substitution comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more non-peptide amino urea or ureido peptidomimetic residues. That is, the native or parent peptide includes a substitution of alpha-amino acids with non-peptide amino urea or ureido peptidomimetic residues.
  • the hybrid compounds described herein comprise amino urea residues of formula I:
  • R a , R R and R”’ a groups are independently selected from hydrogen, any side chain of a natural amino acid, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic aryl-Cl-C6-alkyl, alkenyl or alkynyl; C1-C6- alkyloxy, aryloxy, heteroaryloxy, thio, Cl-C6-alkylthio, amino, mono ordi-Cl-C6-alkylamino, carboxylic acid, carboxamide mono- or di-Cl-C6-alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, or guanidine.
  • the peptide-oligourea hybrid compounds comprise a substitution comprising at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more non-peptide amino urea or ureido peptidomimetic residues.
  • the hybrid compounds described herein comprise amino urea residues of formula P:
  • R is independently selected from a hydrogen atom, an amino acid side chain, a (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C5-C12) monocyclic or bicyclic aryl, (C5-C14) monocyclic or bicyclic aralkyl, (C5-C14) monocyclic or bicyclic heteroalkyl and (Cl -CIO) monocyclic or bicyclic heteroaryl group comprising up to 5 heteroatoms selected from N, O, and S, said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NC , OH, amidine, benzamidine, imidazole, alkoxy, (C1-C4) alkyl, NH2, CN, trihalomethyl, (C1-C4) acyloxy, (Cl- C4) monoalky lamin
  • the peptide-oligourea hybrid compounds comprise at least 1, 2, 3, 4, 5, 6, or more non-peptide amino urea or ureido peptidomimetic and oligomers thereof, wherein the amino urea residues have a structure selected from the group consisting of:
  • R is independently selected from the group consisting of hydrogen, any side chain of a natural amino acid, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S; mono or bicyclic aryl-Cl-C6-alkyl, alkenyl or alkynyl; Cl-C6-alkyloxy, aryloxy, heteroaryloxy, thio, Cl-C6-alkylthio, amino, mono ordi-Cl-C6-alkylamino, carboxylic acid, carboxamide mono- or di-Cl-C6-alkylcarboxamine, sulfonamide, urea, mono-di or tri-substituted urea, thiourea, guanidine;
  • R 1 is independently selected from the group consisting of hydrogen, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S;
  • R 2 is independently selected from the group consisting of hydrogen, linear, branched or cyclic Cl-C6-alkyl, alkenyl or alkynyl; mono- or -bicyclic aryl, mono or bicyclic heteroaryl having up to five heteroatoms selected from N, O and S;
  • R 3 together with the carbon and nitrogen atoms to which it is attached independently defines a substituted or unsubstituted, monocyclic or bicyclic C3-C10 heterocyclic ring having one or more N, 0,or S atom(s) as the heteroatom(s); and substitutents on the cycloalkyl, cycloalkenyl or heterocycle moieties are independently selected from the group consisting of linear, branched or cyclic C1-C6 alkyl, aralkyl,, -0-C(0)-NR'R 2 or -
  • N02, -CN, or -halogen.Rl and R2 are each, within context, H or a C1-C6 alkyl group; -wherein R 4 together with the carbon atoms to which it is attached independently defines a
  • V and W are combined , together with the carbon atoms to which they are bonded, and independently define a substituted or unsubstituted, monocyclic or bicyclic C3-C10 cycloalkyl, cycloalkenyl or heterocyclic ring having one or more N, O, or S atom(s) as the heteroatom(s).
  • the peptide-oligourea hybrid compound comprises a substitution of 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25 or more alpha- amino acids of the parent peptide with one or more amino urea residues as described herein.
  • the number of non-peptide oligourea residues is less than the number of alpha-amino acids substituted (i.e., the number of alph-amino acids removed or replaced).
  • the oligourea residues in the substitution comprise proteinaceous side-chains.
  • the peptide-oligourea hybrid compound comprises a number of amino urea residues that is at least one less than the number of alph-amino acids being substituted. In certain embodiments, the peptide-oligourea hybrid compound comprises a number of non-peptide oligourea residues according to the function:
  • X 11 and m are defined as above;
  • X is an alpha-amino acid residue of the parent peptide
  • p is an integer > 2 and q is a non-zero integer at least one less than p.
  • peptide-oligourea hybrid compounds as described herein comprise amino urea substitutions of a native or parent peptide that is a naturally occurring peptide or a peptide derived from a naturally occurring protein.
  • the parent peptide is a non-naturally occurring peptide or peptidomimetic.
  • the parent peptide is glucagon-like peptide-1 (GLP-1).
  • GLP-1 glucagon-like peptide-1
  • the description provides a glucagon-like peptide-1 (GLP- 1) oligourea hybrid compounds.
  • the GLP-1 peptide- oligourea hybrid demonstrates a resistance to dipeptidyl peptidase-4 (DPP-4) in PBS or in serum that is greater than native or naturally occurring GLP-1. In certain embodiments, the GLP-1 peptide-oligourea hybrid demonstrates a resistance to neutral endopeptidase 24.11 (NEP 24.11) in PBS or in serum that is greater than native or naturally occurring GLP-1. In certain embodiments, the GLP-1 peptide-oligourea hybrid demonstrates an EC50 of less than about 10 mM. In still additional embodiments, the GLP-1 peptide-oligourea hybrid demonstrates binding to GLP-1 receptor (GLP-1R). In certain embodiments, the GLP-1 peptide-oligourea hybrid demonstrates bioactivity in a cAMP production assay.
  • DPP-4 dipeptidyl peptidase-4
  • NEP 24.11 neutral endopeptidase 24.11
  • the peptide-oligourea hybrid has a structure selected from the group of SEQ ID NO. 2-24. In certain embodiments, the peptide-oligourea hybrid as a structures selected from SEQ ID NO. 5, 9, 11, 14, 16, 22, 23, or 24.
  • the peptide-oligourea hybrid compound has a secondary structure similar to a native or parent peptide.
  • the secondary structure can act in a fashion similar to that of the native or parent peptide.
  • the secondary structure of the oligourea compound can be biologically active.
  • the secondary structure can act as a receptor ligand, an effector molecule, an agonist, an antagonist, a modulator of protein-protein interactions, an organocatalyst, or an enzyme.
  • the peptide-oligourea hybrid compound may have a secondary structure that provides a function not found in nature.
  • the oligourea compound may be a catalyst with tailored substrate specificity.
  • the peptide-oligourea hybrid compounds comprise a peptide portion (i.e., a sequence of a-amino acid residues) contiguous with or coupled to an oligourea portion (i.e., a sequence of oligourea residues).
  • the peptide portion comprises at least 2 a-amino acids.
  • the oligourea portion comprises a non-peptide oligourea helical foldamer, for example, non-peptide oligourea peptidomimetic residues.
  • the non-peptide oligourea helical foldamer portion can be an aliphatic oligourea.
  • the non-peptide oligourea helical foldamer can be a short amphiphilic a- helicomimetic foldamer, which may include proteinaceous side chains.
  • the peptide portion may comprise an a-amino acid sequence corresponding to a biologically active peptide or a fragment thereof.
  • the peptide-oligourea hybrid compound as described herein is biologically active.
  • the biological activity can stem from the peptide or the oligourea portion.
  • the compounds as described herein are enzymatically active.
  • the compounds as described herein are configured to bind target proteins.
  • the target protein is a cytosolic protein.
  • the target protein is a membrane protein.
  • the membrane protein is a receptor.
  • the receptor is a growth factor receptor or a G-Protein Coupled Receptor (GPCR) or a fragment thereof.
  • GPCR G-Protein Coupled Receptor
  • the peptide-oligourea hybrid is biologically and/or enzymatically active.
  • the description provides peptide-oligourea hybrid compounds that adopt stable secondary structures, including, e.g., linear, cyclic, or helicoidal, tertiary structure, and/or quaternary structures, wherein the hybrids comprise a sequence of amino acids (i.e., a polypeptide) that has been substituted by amino urea residues that are contiguous with or coupled to the peptide backbone.
  • the amino acid sequence comprises a- amino acids.
  • peptide-oligourea hybrid compound comprises two or more, e.g., 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30 or more, non-peptide amino urea residues as described herein representing a substitution of two or more amino acids from the native or parental peptide.
  • the peptide-oligourea hybrid compound comprises an oligourea portion contiguous with or covalently linked or joined to at least one of the amino terminus (N’), the carboxyl terminus (C’), within the peptide sequence or a combination thereof.
  • the peptide-oligourea hybrid compound comprises an oligourea portion covalently linked or joined to the C’ of the peptide portion.
  • the peptide-oligourea hybrid compound comprises an oligourea portion covalently linked or coupled to the peptide backbone downstream from the N’ and upstream of the C’ peptide portions.
  • the peptide-oligourea hybrid compound comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 ,17, 18 ,19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38 ,39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63 ,64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75,
  • amino urea residues of the described peptide-oligourea hybrid compounds are joined in a chain that is bound at both ends to peptide potions.
  • the peptide-oligourea hybrid compound comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16 ,17, 18 ,19, 20, 21, 22, 23,
  • the description provides oligourea compounds and peptide- oligourea hybrid compounds as described herein further comprising at least one additional chemical modification.
  • the chemical modification includes at least one of, for example, acetylation, phosphorylation, methylation, glycosylation, prenylation, isoprenylation, farnesylation, geranylation, pegylation, a disulfide bond, or combination thereof.
  • the description provides a pharmaceutical composition comprising a peptide-oligourea hybrid as described herein, and a pharmaceutically acceptable excipient.
  • the pharmaceutical composition comprises an effective amount of a peptide-oligourea hybrid as described herein.
  • the effective amount is a therapeutically effective amount or a synergistically effective amount.
  • compositions as described herein including pharmaceutically acceptable salts thereof are useful for the preparation of a medicament and/or the treatment of disease in a subject.
  • a salt of a compound is desired and the compound/composition is produced in the form of the desired salt, it can be subjected to purification as such.
  • the compound/composition is dissolved or suspended in a suitable organic solvent, followed by addition of an acid or a base to form a salt.
  • the description provides compositions comprising an effective amount of a peptide-oligourea hybrid as described herein, and a pharmaceutically acceptable carrier or excipient.
  • the compounds or compositions of the description may optionally be administered with at least one of a pharmaceutically acceptable excipient, pharmacologically active agent or a combination thereof.
  • a pharmaceutically acceptable excipient pharmacologically active agent or a combination thereof.
  • novel, unnatural peptidomimetics are resistant or wholly immune to peptidase and protease degradation and are conformationally restrained. Thus, they are useful as tools to model peptide and protein conformations in aqueous solutions.
  • the compounds are also useful as non-enzymatically degradable probes to mimic protein behavior in solution.
  • the description further provides the compositions comprising an effective amount of a chimeric compound as described herein, and a pharmaceutically acceptable carrier or excipient.
  • Certain compounds or composition of the description and their salts may exist in more than one crystal form and the present disclosure includes each crystal form and mixtures thereof. Certain compounds/compositions of the disclosure and their salts may also exist in the form of solvates, for example hydrates, and the present disclosure includes each solvate and mixtures thereof.
  • compositions of the disclosure may contain one or more chiral centers, and exist in different optically active forms.
  • compounds/compositions of the disclosure contain one chiral center, the compounds/compositions exist in two enantiomeric forms and the present disclosure includes both enantiomers and mixtures of enantiomers, such as racemic mixtures.
  • the enantiomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts which may be separated, for example, by crystallization; formation of diastereoisomeric derivatives or complexes which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic esterification; or gas- liquid or liquid chromatography in a chiral environment, for example on a chiral support for example silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step may be used to liberate the desired enantiomeric form.
  • specific enantiomers may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts or solvents, or by converting one enantiomer into the other by asymmetric transformation.
  • a compound or composition of the description contains more than one chiral center, it may exist in diastereoisomeric forms.
  • the diastereoisomeric compounds may be separated by methods known to those skilled in the art, for example chromatography or crystallization and the individual enantiomers may be separated as described above.
  • the present disclosure includes each diastereoisomer of compounds of the disclosure and mixtures thereof.
  • Certain compounds of the disclosure may exist in different tautomeric forms or as different geometric isomers, and the present disclosure includes each tautomer and/or geometric isomer of compounds of the disclosure and mixtures thereof.
  • Certain compounds or compositions of the disclosure may exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
  • the present disclosure includes each conformational isomer of compounds of the disclosure and mixtures thereof.
  • Certain compounds of the disclosure may exist in zwitterionic form and the present disclosure includes each zwitterionic form of compounds of the disclosure and mixtures thereof.
  • the present disclosure encompasses all possible isomers including tautomers and mixtures thereof. Where chiral carbons lend themselves to two different enantiomers, both enantiomers are contemplated as well as procedures for separating the two enantiomers.
  • the present disclosure also relates to pharmaceutically acceptable salts, racemates, and optical isomers thereof.
  • the compounds of this disclosure typically contain one or more chiral centers. Accordingly, this disclosure is intended to include racemic mixtures, diasteromers, enantiomers and mixture enriched in one or more steroisomer.
  • the scope of the disclosure as described and claimed encompasses the racemic forms of the compounds as well as the individual enantiomers and non-racemic mixtures thereof.
  • pharmaceutically acceptable salt is used throughout the specification to describe, where applicable, a salt form of one or more of the compounds or prodrugs described herein which are presented to increase the solubility of the compound in the gastic juices of the patient's gastrointestinal tract in order to promote dissolution and the bioavailability of the compounds.
  • Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids, where applicable. Suitable salts include those derived from alkali metals such as potassium and sodium, alkaline earth metals such as calcium, magnesium and ammonium salts, among numerous other acids and bases well known in the pharmaceutical art. Sodium and potassium salts are particularly preferred as neutralization salts of the phosphates according to the present disclosure.
  • the description provides pharmaceutically acceptable salts of the modified peptides as described herein, which retain the biological effectiveness and properties of the parent compounds and which are not biologically or otherwise harmful as the dosage administered.
  • the compounds of this disclosure are capable of forming both acid and base salts by virtue of the presence of amino and carboxy groups respectively.
  • a "pharmaceutically acceptable counterion” is an ionic portion of a salt that is not toxic when released from the salt upon administration to a recipient.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free base forms.
  • Acids commonly employed to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid, as well as organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascorbic, maleic, besylic, fumaric, gluconic, glucuronic, formic, glutamic, methanesulfonic, ethanesulfonic, benzenesulfonic, lactic, oxalic, parabromophenylsulfonic, carbonic, succinic, citric, benzoic and acetic acid, and related inorganic and organic acids.
  • inorganic acids such as hydrogen bisulfide, hydrochloric, hydrobromic, hydroiodic, sulfuric and phosphoric acid
  • organic acids such as para-toluenesulfonic, salicylic, tartaric, bitartaric, ascor
  • Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, sub erate , sebacate, fumarate, maleate, butyne-I,4-dioate, hexyne-I,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, terephthalate, sulfonate, xylenesulfonate, phenylacetate, phenyl
  • Preferred pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.
  • Suitable bases for forming pharmaceutically acceptable salts with acidic functional groups include, but are not limited to, hydroxides of alkali metals such as sodium, potassium, and lithium; hydroxides of alkaline earth metal such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, and organic amines, such as unsubstituted or hydroxy-substituted mono-, di-, or trialkylamines; dicyclohexylamine; tributyl amine; pyridine; N-methyl,N-ethylamine; diethylamine; triethylamine; mono-, bis-, or tris-(2-hydroxy-Iower alkyl amines), such as mono-, bis-, or tris- (2-hydroxyethyl)amine, 2-hydroxy-tert-but
  • prodrug forms of the above described peptide- oligourea hybrid compounds, wherein the prodrug is metabolized in vivo to produce an analog or derivative as set forth above. Indeed, some of the described compounds may be a prodrug for another analog or derivative.
  • prodrug is well understood in the art and refers to an agent which is converted into the parent drug in vivo by some physiological chemical process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). For example, see Remington 's Pharmaceutical Sciences. 1980, vol. 16, Mack Publishing Company, Easton, Pa., 61 and 424.
  • Pro-drugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have improved solubility in pharmacological compositions over the parent drug.
  • An example, without limitation, of a pro drug would be a compound of the present disclosure wherein it is administered as an ester (the "pro-drug") to facilitate transmittal across a cell membrane where water solubility is not beneficial, but then it is metabolically hydrolyzed to the carboxylic acid once inside the cell where water solubility is beneficial.
  • Pro-drugs have many useful properties.
  • a pro drug may be more water soluble than the ultimate drug, thereby facilitating intravenous administration of the drug.
  • a pro-drug may also have a higher level of oral bioavailability than the ultimate drug. After administration, the prodrug is enzymatically or chemically cleaved to deliver the ultimate drug in the blood or tissue.
  • Exemplary pro-drugs upon cleavage release the corresponding free acid, and such hydrolyzable ester-forming residues of the compounds of this disclosure include but are not limited to carboxylic acid substituents (e.g., -C(0)2H or a moiety that contains a carboxylic acid) wherein the free hydrogen is replaced by (Cl -C4)alkyl, (Cz-C12)alkanoyloxymethyl, (C4-C9)l- (alkanoyloxy)ethyl, I-methyl-l-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1 -(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, I-methyl-1-10 (alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon
  • Other exemplary pro-drugs release an alcohol or amine of a compound of the disclosure wherein the free hydrogen of a hydroxyl or amine substituent is replaced by (Cl - C6)alkanoyloxymethyl, l-((Cl-C6)alkanoyloxy)ethyl, I-methyl-l-((Cl-C6)alkanoyloxy)ethyl, (Cl -C6)alkoxycarbonyl-oxymethyl, N-(C1 -C6)alkoxycarbonylamino- 20 methyl, succinoyl, (Cl - C6)alkanoyl, a-amino(C l-C4)alkanoyl, arylactyl and a-aminoacyl, or a-aminoacyl-a-aminoacyl wherein said a-aminoacyl moieties are independently any of the naturally occurring L-amino acids found in proteins, -P(0)(OH)2'
  • protecting group means temporary substituents which protect a potentially reactive functional group from undesired chemical transformations.
  • protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively.
  • the field of protecting group chemistry has been reviewed (Greene, T.W.; Wuts, P.G.M. Protective 30 Groups in Organic Synthesis, 2nd ed.; Wiley: New York, 1991). Protected forms of the inventive compounds are included within the scope of this disclosure.
  • chemically protected form pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group). It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form.
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • a carboxylic acid group may be protected as an ester or an amide, for example, as: a benzyl ester; a t-butyl ester; a methyl ester; or a methyl amide.
  • the compounds disclosed herein can be used in the treatment of disorders associated with pathogen infection.
  • Disorders associated with infection by pathogens include, but are not limited to, infection by viruses (DNA viruses, RNA viruses, animal viruses, and the like), bacteria (e.g., gram positive bacteria, gram negative bacteria, acid-fast bacteria, and the like), fungi, parasitic microbes, nematodes, and the like.
  • viruses DNA viruses, RNA viruses, animal viruses, and the like
  • bacteria e.g., gram positive bacteria, gram negative bacteria, acid-fast bacteria, and the like
  • fungi e.g., parasitic microbes, nematodes, and the like.
  • pharmaceutically acceptable derivative is used throughout the specification to describe any pharmaceutically acceptable prodrug form (such as an ester, amide other prodrug group) which, upon administration to a patient, provides directly or indirectly the present compound or an active metabolite of the present compound.
  • pharmaceutically acceptable derivative such as an ester, amide other prodrug group
  • independently is used herein to indicate that the variable, which is independently applied, varies independently from application to application.
  • Suitable routes for administration include oral, peroral, rectal, vassal, topical (including ocular, buccal and sublingual), vaginal and parental (including subcutaneous, intramuscular, intravitreous, intravenous, intradermal, intrathecal and epidural).
  • the preferred route of administration will depend upon the condition of the patient, the toxicity of the compound and the site of infection, among other considerations known to the clinician.
  • the therapeutic composition of the disclosure comprises about 1% to about 95% of the active ingredient, single-dose forms of administration preferably comprising about 20% to about 90% of the active ingredient and administration forms which are not single-dose preferably comprising about 5% to about 20% of the active ingredient.
  • Unit dose forms are, for example, coated tablets, tablets, ampoules, vials, suppositories or capsules.
  • Other forms of administration are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions and the like. Examples are capsules containing from about 0.05 g to about 1.0 g of the active ingredient.
  • compositions of the present disclosure are prepared in a manner known per se, for example by means of convential mixing, granulating, coating, dissolving or lyophilizing processes.
  • solutions of the active ingredient, and in addition also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions, are used, it being possible for these to be prepared before use, for example in the case of lyophilized compositions which comprise the active substance by itself or together with a carrier, for example mannitol.
  • the pharmaceutical compositions can be sterilized and/or comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizing agents, salts for regulating the osmotic pressure and/or buffers, and they are prepared in a manner known per se, for example by means of convential dissolving or lyophibzing processes.
  • the solutions or suspensions mentioned can comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.
  • Pharmaceutically acceptable forms include, for example, a gel, lotion, spray, powder, pill, tablet, controlled release tablet, sustained release tablet, rate controlling release tablet, enteric coating, emulsion, liquid, salts, pastes, jellies, aerosols, ointments, capsules, gel caps, or any other suitable form that will be obvious to one of ordinary skill in the art.
  • Suspensions in oil comprise, as the oily component, the vegetable, synthetic or semi-synthetic oils customary for injection purposes.
  • Oils which may be mentioned are, in particular, liquid fatty acid esters which contain, as the acid component, a long-chain fatty acid having 8-22, in particular 12-22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidinic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, euric acid, brasidic acid or linoleic acid, if appropriate with the addition of antioxidants, for example vitamin E, .beta.- carotene or 3,5-di-tert-butyl-4-hydroxytoluene.
  • the alcohol component of these fatty acid esters has not more than 6 carbon atoms and is mono- or polyhydric, for example mono-, di- or trihydric alcohol, for example methanol, ethanol, propanol, butanol, or pentanol, or isomers thereof, but in particular glycol and glycerol.
  • Fatty acid esters are therefore, for example: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375” (polyoxyethylene glycerol trioleate from Gattefosee, Paris), "Labrafil M 1944 CS” (unsaturated polyglycolated glycerides prepared by an alcoholysis of apricot kernel oil and made up of glycerides and polyethylene glycol esters; from Gattefosee, Paris), “Labrasol” (saturated polyglycolated glycerides prepared by an alcoholysis of TCM and made up of glycerides and polyethylene glycol esters; from Gattefosee, Paris) and/or "Miglyol 812" (triglyceride of saturated fatty acids of chain length C8 to C12 from Huls AG, Germany), and in particular vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame
  • compositions for oral use can be obtained by combining the active ingredient with one or more solid carriers, if appropriate granulating the resulting mixture, and, if desired, processing the mixture or granules to tablets or coated tablet cores, if appropriate by addition of additional excipients.
  • Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol cellulose preparations and/or calcium phosphates, for example tricalcium phosphate, or calcium hydrogen phosphate, and furthermore binders, such as starches, for example maize, wheat, rice or potato starch, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinyl-pyrrolidine, and/or, if desired, desintegrators, such as the above mentioned starches, and furthermore carboxymethyl-starch, cross-linked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate.
  • fillers such as sugars, for example lactose, sucrose, mannitol or sorbitol cellulose preparations and/or calcium phosphates, for example tricalcium phosphate, or calcium hydrogen phosphate
  • binders such as starches, for example maize,
  • Additional excipients are, in particular, flow regulators and lubricants, for example salicylic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • flow regulators and lubricants for example salicylic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof.
  • Coated tablet cores can be provided with suitable coatings which, if appropriate, are resistant to gastric juice, the coatings used being, inter alia, concentrated sugar solutions, which, if appropriate, comprise gum arabic, talc, polyvinylpyrrolidine, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings which are resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate.
  • controlled release it is meant for purposes of the present disclosure that therapeutically active compound is released from the preparation at a controlled rate or at a specific site, for example, the intestine, or both such that therapeutically beneficial blood levels (but below toxic levels) are maintained over an extended period of time, e.g., providing a 12 hour or a 24 hour dosage form.
  • rate controlling polymer includes hydrophilic polymers, hydrophobic polymers or mixtures of hydrophilic and/or hydrophobic polymers that are capable of retarding the release of the compounds in vivo.
  • many of the same polymers can be utilized to create an enteric coating of a drug, drug suspension, or drug matrix. It is within the skill of those in the art to modify the coating thickness, permeability, and dissolution characteristics to provide the desired controlled release profile (e.g., drug release rate and locus) without undue experimentation.
  • Suitable controlled release polymers to be used in this disclosure include hydroxyalkylcellulose, such as hydroxypropylcellulose and hydroxypropylmethyl- cellulose; poly(ethylene)oxide; alkylcellulose such as ethycellulose and methylcellulose; carboxymethylcellulose; hydrophilic cellulose derivatives; polyethylene glycol; polyvinylpyrrolidone; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; polyvinylacetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; poly(alkyl methacrylate); and poly (vinyl acetate).
  • Other suitable hydrophobic polymers include polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, zein, waxes, shellac and hydrogenated vegetable oils.
  • the controlled release preparation of this disclosure contains about 5 and 75% by weight, preferably about 20 and 50% by weight, more preferably about 30 to 45% by weight controlled release polymer(s) and about 1 to 40% by weight, preferably about 3 to 25% by weight active compounds.
  • the controlled release preparation according to the disclosure can preferably include auxiliary agents, such as diluents, lubricants and/or melting binders.
  • the excipients are selected to minimize the water content of the preparation.
  • the preparation includes an antioxidant.
  • Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing.
  • the diluent is suitably a water soluble diluent.
  • examples of diluents include microcrystalline cellulose such as Avicel phi 12, Avicel pHlOl and Avicel pH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose DCL 21 ; dibasic calcium phosphate such as Emcompress; mannitol; starch; sorbitol; sucrose; and glucose. Diluents are carefully selected to match the specific formulation with attention paid to the compression properties.
  • Suitable lubricants including agents that act on the flowability of the powder to be compressed are, for example, colloidal silicon dioxide such as Aerosil 200; talc; stearic acid, magnesium stearate, and calcium stearate.
  • Suitable low temperature melting binders include polyethylene glycols such as PEG 6000; cetostearyl alcohol; cetyl alcohol; polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene stearates; poloxamers; and waxes.
  • an antioxidant compound can be included.
  • Suitable antioxidants include sodium metabisulfite; tocopherols such as alpha, beta, or delta-tocopherol tocopherol esters and alpha-tocopherol acetate; ascorbic acid or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; alkyl gallates such as propyl gallate, Tenox PG, Tenox s-1; sulphites or a pharmaceutically acceptable salt thereof; BHA; BHT; and monothioglycerol.
  • the controlled release preparation according to the disclosure preferably can be manufactured by blending the compounds with the controlled release polymer(s) and auxiliary excipients followed by direct compression.
  • Other methods for manufacturing the preparation include melt granulation.
  • Preferred melt granulation techniques include melt granulation together with the rate controlling polymer(s) and diluent(s) followed by compression of the granules and melt granulation with subsequent blending with the rate controlling polymer(s) and diluents followed by compression of the blend.
  • the blend and/or granulate can be screened and/or mixed with auxiliary agents until an easily flowable homogeneous mixture is obtained.
  • Oral dosage forms of the controlled release preparation according to the disclosure can be in the form of tablets, coated tablets, enterically coated tablets or can be multiparticulate, such as in the form of pellets or mini-tablets.
  • capsules such as hard or soft gelatin capsules, can contain the multiparticulates.
  • the multiparticulate oral dosage forms can comprise a blend of at least two populations of pellets or mini-tablets having different controlled-release in vitro and/or in vivo release profiles.
  • one of the pellet or mini-tablet populations can comprise immediate release multiparticulate, such as multiparticulates formed by conventional means.
  • the controlled release matrix tablets or multiparticulates of this disclosure can be coated with a controlled release polymer layer so as to provide additional controlled release properties.
  • Suitable polymers that can be used to form this controlled release layer include the rate controlling polymers listed above.
  • the tablets, pellets or mini-tablets according to the disclosure can be provided with a light-protective and/or cosmetic film coating, for example, film-formers, pigments, anti-adhesive agents and plasticizers.
  • a film former may consist of fast dissolving constituents, such as low-viscosity hydroxypropylmethylcelluose, for example Methocel E5 or D14 or Pharmacoat 606 (Shin-Etsu).
  • the film coating may also contain excipients customary in film-coating procedures, such as light-protective pigments, for example iron oxide, or titanium dioxide, anti-adhesive agents, for example talc, and also suitable plasticizers such as PEG 400, PEG 6000, and diethyl phthalate or triethyl citrate.
  • light-protective pigments for example iron oxide, or titanium dioxide
  • anti-adhesive agents for example talc
  • suitable plasticizers such as PEG 400, PEG 6000, and diethyl phthalate or triethyl citrate.
  • the controlled release polymer of this disclosure may consist of a hydrogel matrix.
  • the compounds can be compressed into a dosage form containing a rate controlling polymer, such as HPMC, or mixture of polymers which when wet will swell to form a hydrogel.
  • a rate controlling polymer such as HPMC
  • HPMC high density polyethylene glycol
  • the rate of release from this dosage form is controlled both by diffusion from the swollen tablet mass and by erosion of the tablet surface over time.
  • the rate of release may be controlled both by the amount of polymer per tablet and by the inherent viscosities of the polymers used.
  • Dyes or pigments can be admixed to the tablets or coated tablet coatings, for example for identification or characterization of different doses of active ingredient.
  • compositions which can be used orally, are also hard capsules of gelatin and soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard capsules can contain the active ingredient in the form of granules, mixed for example with fillers, such as maize starch, binders and/or lubricants, such as talc or magnesium stearate, and stabilizers if appropriate.
  • the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as greasy oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it being likewise possible to add stabilizers and detergents, for example of the polyethylene sorbitan fatty acid ester type.
  • suitable liquid excipients such as greasy oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it being likewise possible to add stabilizers and detergents, for example of the polyethylene sorbitan fatty acid ester type.
  • compositions which can be used rectally, are, for example, suppositories that comprise a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, naturally occurring or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • compositions which are suitable for parenteral administration are aqueous solutions of an active ingredient in water-soluble form, for example of water-soluble salt, or aqueous injection suspensions, which comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and if appropriate stabilizers.
  • the active ingredient can also be present here in the form of a lyophilisate, if appropriate together with excipients, and be dissolved before parenteral administration by addition of suitable solvents.
  • Solutions such as are used, for example, for parental administration can also be used as infusion solutions.
  • Preferred preservatives are, for example.
  • Antioxidants such as ascorbic acid, or microbicides, such as sorbic or benzoic acid.
  • Ointments are oil-in-water emulsions, which comprise not more than 70%, but preferably 20-50% of water or aqueous phase.
  • the fatty phase consists, in particular, hydrocarbons, for example vaseline, paraffin oil or hard paraffin's, which preferably comprise suitable hydroxy compounds, such as fatty alcohol's or esters thereof, for example cetyl alcohol or wool wax alcohols, such as wool wax, to improve the water-binding capacity.
  • Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate.
  • Additives to the aqueous phase are, for example, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and odoriferous substances.
  • humectants such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and odoriferous substances.
  • Fatty ointments are anhydrous and comprise, as the base, in particular, hydrocarbons, for example paraffin, vaseline or paraffin oil, and furthermore naturally occurring or semi-synthetic fats, for example hydrogenated coconut-fatty acid triglycerides, or, preferably, hydrogenated oils, for example hydrogenated groundnut or castor oil, and furthermore fatty acid partial esters of glycerol, for example glycerol mono- and/or distearate, and for example, the fatty alcohols. They also contain emulsifiers and/or additives mentioned in connection with the ointments which increase uptake of water.
  • hydrocarbons for example paraffin, vaseline or paraffin oil
  • furthermore naturally occurring or semi-synthetic fats for example hydrogenated coconut-fatty acid triglycerides, or, preferably, hydrogenated oils, for example hydrogenated groundnut or castor oil, and furthermore fatty acid partial esters of glycerol, for example glycerol mono- and/
  • Creams are oil-in-water emulsions, which comprise more than 50% of water.
  • Oily bases used are, in particular, fatty alcohols, for example lauryl, cetyl or stearyl alcohols, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example vaseline (petrolatum) or paraffin oil.
  • Emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example fatty acid esters of polyalcohols or ethyleneoxy adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene sorbitan fatty esters (Tweens), and furthermore polyoxyethylene fatty alcohol ethers or polyoxyethylene fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl stearyl alcohol or stearyl alcohol.
  • corresponding nonionic emulsifiers for example fatty acid esters of polyalcohols or ethyleneoxy adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene
  • Additives to the aqueous phase are, inter alia, agents which prevent the creams from drying out, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and furthermore preservatives and odoriferous substances.
  • polyalcohols such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and furthermore preservatives and odoriferous substances.
  • Pastes are creams and ointments having secretion-absorbing powder constituents, such as metal oxides, for example titanium oxide or zinc oxide, and furthermore talc and/or aluminum silicates, which have the task of binding the moisture or secretions present.
  • secretion-absorbing powder constituents such as metal oxides, for example titanium oxide or zinc oxide, and furthermore talc and/or aluminum silicates, which have the task of binding the moisture or secretions present.
  • Foams are administered from pressurized containers and they are liquid oil-in water emulsions present in aerosol for.
  • halogenated hydrocarbons such as chlorofluoro-lower alkanes, for example dichlorofluoromethane and dichlorotetrafluoroethane, or, preferably, non-halogenated gaseous hydrocarbons, air, N.sub.2 O, or carbon dioxide are used.
  • the oily phases used are, inter alia, those mentioned above for ointments and creams, and the additives mentioned there are likewise used.
  • Tinctures and solutions usually comprise an aqueous-ethanolic base to which, humectants for reducing evaporation, such as polyalcohols, for example glycerol, glycols and/or polyethylene glycol, and re-oiling substances, such as fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture to substitute the fatty substances removed from the skin with the ethanol, and, if necessary, other excipients and additives, are admixed.
  • humectants for reducing evaporation such as polyalcohols, for example glycerol, glycols and/or polyethylene glycol
  • re-oiling substances such as fatty acid esters with lower polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture to substitute the fatty substances removed from the skin with the ethanol, and, if necessary, other excipients and additives, are
  • the description provides co-adminstered formulations comprising a peptide-oligourea hybrid compound as described herein, and at least one additional thereapeutic agent.
  • co-administration and “co-administering” or“combination therapy” refer to both concurrent administration (administration of two or more therapeutic agents at the same time) and time varied administration (administration of one or more therapeutic agents at a time different from that of the administration of an additional therapeutic agent or agents), as long as the therapeutic agents are present in the patient to some extent, preferably at effective amounts, at the same time.
  • one or more of the present compounds described herein are coadministered in combination with at least one additional bioactive agent.
  • the co-administration of compounds results in synergistic activity and/or therapy.
  • the agent to be co-administered is selected from the group comprising anti-cancer agents, antiviral agents (especially including anti-HIV agents and anti-HCV agents), antimicrobial agents, and antifungal agents.
  • the anti-cancer agents can include, e.g., everolimus, trabectedin, abraxane, TLK 286, AV-299, DN-101, pazopanib, GSK690693, RTA 744, ON 0910.Na, AZD 6244 (ARRY-142886), AMN-107, TKI-258, GSK461364, AZD 1152, enzastaurm, vandetamb, ARQ-197, MK-0457, MLN8054, PHA- 739358, R-763, AT-9263, a FLT-3 inhibitor, a VEGFR inhibitor, an EGFR TK inhibitor, an aurora kinase inhibitor, a PIK-1 modulator, a Bel -2 inhibitor, an HD AC inhbitor, a c-MET inhibitor, a PARP inhibitor, a Cdk inhibitor, an EGFR TK inhibitor, an IGFR-TK inhibitor, an anti-HGF antibody, a PI3 kin
  • disease state or condition is used to describe any disease state or condition wherein protein dysregulation (i.e., the amount of protein expressed in a patient is elevated) occurs and where degradation of one or more proteins in a patient may provide beneficial therapy or relief of symptoms to a patient in need thereof. In certain instances, the disease state or condition may be cured.
  • the description provides a method of treating a disease, comprising administering to a subject in need thereof a composition comprising an effective amount of a peptide-oligourea hybrid as described herein, or a pharmaceutical formulation comprising the same and a pharmaceutically acceptable excipient, wherein composition is effective at treating or ameliorating at least one symptom of the disease.
  • the disease is a metabolic disorder.
  • the disease is diabetes.
  • treatment includes any treatment of a condition or disease in an animal, particularly a mammal, more particularly a human, and includes: (i) preventing the disease or condition from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e. arresting its development; relieving the disease or condition, i.e. causing regression of the condition; or (iii) ameliorating or relieving the conditions caused by the disease, i.e. symptoms of the disease.
  • the term“effective” is used to describe an amount of a compound, composition or component which, when used within the context of its intended use, effects an intended result.
  • the term “therapeutically effective amount” refers to that amount which is sufficient to effect treatment, as defined herein, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the subject and disease state being treated, the severity of the affliction and the manner of administration, and may be determined routinely by one of ordinary skill in the art.
  • the disclosure also relates to a process or method for treatment of disease states.
  • the oligourea compounds or chimeric compounds can be administered prophylactically or therapeutically as such or in the form of pharmaceutical compositions, preferably in an amount, which is effective against the diseases mentioned.
  • the compounds With a warm-blooded animal, for example a human, requiring such treatment, the compounds are used, in particular, in the form of pharmaceutical composition.
  • a daily dose of about 0.1 to about 5 g, preferably 0.5 g to about 2 g, of a compound of the present disclosure is administered here for a body weight of about 70 kg.
  • the description provides methods of treating a disease or disorder or ameliorating the effects of the same comprising the steps of administering to an individual in need thereof, a composition comprising an effective amount of a chimeric compound or a oligourea compound as described herein, and a pharmaceutically acceptable carrier or excipient, wherein the composition is effective for treating, preventing or ameliorating the effects of the disease or disorder.
  • the compounds or compositions described above are used for the manufacture of a medication for use in the treatment of a disease, disorder or condition.
  • the term“disease involving deregulation of cell proliferation and/or angiogenesis” means, in the context of the disclosure, any human or animal disease affecting one or more organs.
  • Disease states of conditions which may be treated using compounds or compositions according to the present disclosure include, for example, asthma, autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity, refractive error, infertility, Angelman syndrome, Canavan disease, Coeliac disease, Charcot- Marie-Tooth disease, Cystic fibrosis, Duchenne muscular dystrophy, Haemochromatosis, Haemophilia, Klinefelter's syndrome, Neurofibromatosis, Phenylketonuria, Polycystic kidney disease, (PKDl) or 4 (PKD2) Prader-Willi syndrome, Sickle-cell disease, Tay-Sachs disease, Turner syndrome.
  • autoimmune diseases such as multiple sclerosis, various cancers, ciliopathies, cleft palate, diabetes, heart disease, hypertension, inflammatory bowel disease, mental retardation, mood disorder, obesity,
  • Other disease states or conditions which may be treated by compounds or compositions according to the present disclosure include Alzheimer's disease, Amyotrophic lateral sclerosis (Lou Gehrig’s disease), Anorexia nervosa, Anxiety disorder, Atherosclerosis, Attention deficit hyperactivity disorder, Autism, Bipolar disorder, Chronic fatigue syndrome, Chronic obstructive pulmonary disease, Crohn's disease, Coronary heart disease, Dementia, Depression, Diabetes mellitus type 1, Diabetes mellitus type 2, Epilepsy, Guillain-Barre syndrome, Irritable bowel syndrome, Lupus, Metabolic syndrome, Multiple sclerosis, Myocardial infarction, Obesity, Obsessive-compulsive disorder, Panic disorder, Parkinson's disease, Psoriasis, Rheumatoid arthritis, Sarcoidosis, Schizophrenia, Stroke, Thromboangiitis obliterans, Tourette syndrome, Vasculitis.
  • Alzheimer's disease Amyotrophic lateral
  • Other exemplary diseases include, but are not limited to, rheumatoid arthritis, osteoarthritis, juvenile chronic arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis, spondyloarthropathy, systemic lupus erythematosus, Crohn's disease, ulcerative colitis, inflammatory bowel disease, insulin dependent diabetes mellitus, thyroiditis, asthma, allergic diseases, psoriasis, dermatitis scleroderma, atopic dermatitis, graft versus host disease, organ transplant rejection, acute or chronic immune disease associated with organ transplantation, sarcoidosis, atherosclerosis, disseminated intravascular coagulation, Kawasaki's disease, Grave's disease, nephrotic syndrome, chronic fatigue syndrome, Wegener's granulomatosis, Henoch- Schoenlein purpurea, microscopic vasculitis of the kidneys, chronic active hepatitis, uveitis, s
  • the human antibodies, and antibody portions of the disclosure can be used to treat autoimmune diseases, in particular those associated with inflammation, including, rheumatoid spondylitis, allergy, autoimmune diabetes, autoimmune uveitis.
  • Still additional disease states or conditions which can be treated by compounds or compositions according to the present disclosure include aceruloplasminemia, Achondrogenesis type II, achondroplasia, Acrocephaly, Gaucher disease type 2, acute intermittent porphyria, Canavan disease, Adenomatous Polyposis Coli, ALA dehydratase deficiency, adenylosuccinate lyase deficiency, Adrenogenital syndrome, Adrenoleukodystrophy, ALA-D porphyria, ALA dehydratase deficiency, Alkaptonuria, Alexander disease, Alkaptonuric ochronosis, alpha 1- antitrypsin deficiency, alpha- 1 proteinase inhibitor, emphyse
  • cancer is used throughout the specification to refer to the pathological process that results in the formation and growth of a cancerous or malignant neoplasm, i.e., abnormal tissue that grows by cellular proliferation, often more rapidly than normal and continues to grow after the stimuli that initiated the new growth cease.
  • Malignant neoplasms show partial or complete lack of structural organization and functional coordination with the normal tissue and most invade surrounding tissues, metastasize to several sites, and are likely to recur after attempted removal and to cause the death of the patient unless adequately treated.
  • neoplasia is used to describe all cancerous disease states and embraces or encompasses the pathological process associated with malignant hematogenous, ascitic and solid tumors.
  • Exemplary cancers which may be treated by the present compounds either alone or in combination with at least one additional anti-cancer agent include squamous-cell carcinoma, basal cell carcinoma, adenocarcinoma, hepatocellular carcinomas, and renal cell carcinomas, cancer of the bladder, bowel, breast, cervix, colon, esophagus, head, kidney, liver, lung, neck, ovary, pancreas, prostate, and stomach; leukemias; benign and malignant lymphomas, particularly Burkitfs lymphoma and Non-Hodgkin's lymphoma; benign and malignant melanomas; myeloproliferative diseases; sarcomas, including Ewing's sarcoma, hemangiosarcoma, Kaposi's sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytomas, oligodendrogli
  • Additional cancers which may be treated using compounds according to the present disclosure include, for example, T-lineage Acute lymphoblastic Leukemia (T-ALL), T- lineage lymphoblastic Lymphoma (T-LL), Peripheral T-cell lymphoma, Adult T-cell Leukemia, Pre-B ALL, Pre-B Lymphomas, Large B-cell Lymphoma, Burkitts Lymphoma, B-cell ALL, Philadelphia chromosome positive ALL and Philadelphia chromosome positive CML.
  • T-ALL T-lineage Acute lymphoblastic Leukemia
  • T-LL T- lineage lymphoblastic Lymphoma
  • Peripheral T-cell lymphoma Peripheral T-cell lymphoma
  • Adult T-cell Leukemia Pre-B ALL
  • Pre-B Lymphomas Large B-cell Lymphoma
  • Burkitts Lymphoma B-cell ALL
  • Philadelphia chromosome positive ALL Philadelphia chromosome positive CML.
  • the methods herein include administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce a desired effect. Identifying a subject in need of such treatment can be in the judgment of the subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).
  • the therapeutic methods of the disclosure which include prophylactic treatment, in general comprise administration of a therapeutically effective amount of at least one of the compounds herein, such as a compound of the formulae herein to a subject (e.g., animal, human) in need thereof, including a mammal, particularly a human.
  • Such treatment will be suitably administered to subjects, particularly humans, suffering from, having, susceptible to, or at risk for a disease, disorder, or symptom thereof. Determination of those subjects "at risk” can be made by any objective or subjective determination by a diagnostic test or opinion of a subject or health care provider (e.g., genetic test, enzyme or protein marker, Marker (as defined herein), family history, and the like).
  • a diagnostic test or opinion of a subject or health care provider e.g., genetic test, enzyme or protein marker, Marker (as defined herein), family history, and the like.
  • the present description provides methods of making and using the peptide-oligourea hybrid compounds or the oligourea compounds as described herein.
  • the peptide-oligourea hybrid compounds or the oligourea compound as described herein can be used as a diagnostic agent.
  • the disclosure provides a method of monitoring treatment progress.
  • the method includes the step of determining a level of diagnostic marker (Marker) (e.g., any target delineated herein modulated by a compound herein, a protein or indicator thereof, etc.) or diagnostic measurement (e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof associated with protein-expression related disease (including misfolding), in which the subject has been administered a therapeutic amount of a compound or a composition herein sufficient to treat the disease or symptoms thereof.
  • the level of Marker determined in the method can be compared to known levels of Marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status.
  • a second level of Marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy.
  • a pre-treatment level of Marker in the subject is determined prior to beginning treatment according to this disclosure; this pre treatment level of Marker can then be compared to the level of Marker in the subject after the treatment commences, to determine the efficacy of the treatment.
  • the active compound is included in the pharmaceutically acceptable carrier or diluent in an amount sufficient to deliver to a patient a therapeutically effective amount for the desired indication, without causing serious toxic effects in the patient treated.
  • a preferred dose of the active compound for all of the herein-mentioned conditions is in the range from about 10 ng/kg to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally 0.5 to about 25 mg per kilogram body weight of the recipient/patient per day.
  • a typical topical dosage will range from 0.01-5% wt/wt in a suitable carrier.
  • the compound is conveniently administered in any suitable unit dosage form, including but not limited to one containing less than lmg, 1 mg to 3000 mg, preferably 5 to 500 mg of active ingredient per unit dosage form.
  • An oral dosage of about 25-250 mg is often convenient.
  • the active ingredient is preferably administered to achieve peak plasma concentrations of the active compound of about 0.00001-30 mM, preferably about 0.1-30 mM.
  • This may be achieved, for example, by the intravenous injection of a solution or formulation of the active ingredient, optionally in saline, or an aqueous medium or administered as a bolus of the active ingredient. Oral administration is also appropriate to generate effective plasma concentrations of active agent.
  • concentration of active compound in the drug composition will depend on absorption, distribution, inactivation, and excretion rates of the drug as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated.
  • compositions should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • the present description provides methods of making and using the compounds or compositions of the description.
  • the description provides a method of making an oligourea compound composition of the description comprising fabricating a peptide-oligourea hybrid foldamer compound.
  • Peptide-oligourea hybrids design and functional assay Peptide-oligourea hybrid design started with GLP-I-NH2 and the introduction of a glycine in position 2 of GLP-1 instead of alanine (GLP-l-G 2 , Compound 1 and SEQ ID NO. 1) as it is known to prevent DPP-4 degradation. 31-33 We then identified the amount of consecutive amino acid residues that can be replaced by ureido units. This aspect was important considering GLP-1 has key interactions with GLP-1 R at both end of the peptide.
  • the third amino acid side chain seemed to be the least imitable as it is superimposed with a urea nitrogen of the third ureido residue X ll 3.
  • this third ureido residue could mimic the fourth amino acid residue (X4) by changing the substitution pattern (shift to the second methylene - a-C).
  • our model suggested that mimicking the precise projection of a-amino acid side chains was possible although not necessary trivial.
  • Table 1 shows a selection of the most representative results obtained in this study. Interestingly, in most cases the reintroduction of the native side chains improved the potency of the GLP-l-oligourea hybrids. GG2[Y U E U A U ] 14- 17 (9) even gave a better affinity (0.18 nM) than the native peptide 1 (0.24 nM). It is noteworthy that hybrids GG2 [D ua A u A u ] 9-12 (2, 13 nM) and GG2[F ua I u A u ] 22 - 25 (16, 62 nM) which contain native side chains and shifted substitution pattern still preserve substantial affinity with GLP-1R, although with over a hundred fold loss compared to the native peptide.
  • NEP 24.11 Neuronal endopeptidase 24.11, also known as Neprilysin, CD 10, MME, and CALLA
  • NEP 24.11 is an unspecific membrane protease that quickly cleaves GLP-1 at multiple sites. 35 It was showed that a GLP-1 analogue with improved half-life in a NEP 24.11 degradation assay had prolonged action in mice, therefore making this assay relevant to evaluate the potential efficacy in vivo of our compounds. 40
  • mouse plasma was also utilized to assess the stability or our compounds.
  • Semaglutide is a GLP-1 analogue with an 2-aminoisobutyric (Aib) in position 2 and a Cl 8 chain linked to K 20 through a small PEG spacer which was accepted by the FDA in 2018 for the treatment of diabetes as a once weekly treatment and is presently in phase 3 clinical trial for a once daily oral treatment.
  • hybrid 24 which is a semaglutide analogue with an oligourea fragment replacing the four last amino acids (semaglutide- [A U A U A U ] 28 31 ) like in hybrid 22.
  • hybrid 24 was found to be equally potent to semaglutide ( Figures 27A and 27B).
  • the pharmacodynamics properties of 24 were next assessed in a study on db/db mice using FDA approved exenatide, liraglutide and semaglutide as positive controls. A single dose of analogues or placebo was injected intra peritoneal and the blood glucose was followed over time.
  • hybrid 24 and semaglutide (25) were still active while exenatide and liraglutide showed no more significant activity.
  • hybrid 24 and semaglutide (25) showed similar activities in vitro and in vivo ( Figures 38A-38C), it is noteworthy that hybrid 24 displays a longer half-life than semaglutide in mouse plasma (160 vs 11 h, Figures 34A-34C) and pancreatin (3.2 vs 0.63 h, Figures 38C and 35A-35C).
  • GFP-1 R Agonists of GFP-1 R have proved to be potent treatment against type 2 diabetes mellitus and are promising for other indications such as obesity, NASH, and Alzheimer’s disease. It is noteworthy that three hybrids out of the eight tested in mice had significantly prolonged duration of action. This prolonged effect was correlated with both NEP 24.11 and mouse plasma degradation studies, suggesting an increased stabilization towards other peptidases present in the organism. The strategy was then applied to semaglutide, a FDA approved GLP-1 analogue, to generate hybrid 24 and we showed that not only the in vivo activity was preserved, but the stability toward pancreatin was improved opening the way for improvement in oral administration.
  • Each activated monomer (3 equiv) was coupled twice using DIEA (10 equiv) under microwave irradiation (70 °C, 50 W, 20 min) in DMF (4 mL).
  • the reduction of the azido group was performed twice in a mixture of 1 ,4-dioxane/H 2 0 (7:3 v/v) (5 mL) with a 1 M PMe 3 solution in THF (10 equiv) under microwave irradiation (50 °C, 50 W, 30 min). See supplementary data for the remaining steps of the synthesis of 24.
  • the resin was transferred into a syringe with a frit, and washed three times with DMF, three times with CH2CI2 and three times with Et 2 0.
  • Cleavage from the resin was performed using 95% TFA with 2.5% triisopropylsilane and 2.5% water (3 mL).
  • the resin was filtered and discarded. Diethyl ether was added to precipitate the oligomer and the solid was triturated and filtrated.
  • Semi preparative purification of all compound was performed by HPLC using a C18ec column (10 x 250 mm, 5 pm).
  • the standard reference agonist is GLP-1, which is tested in each experiment at several concentrations to generate a concentration-response curve from which its ECso value and SE is calculated using GraphPad Prism.
  • Enzymatic degradation (NEP 24.11).
  • Stock solutions of the oligomers were prepared at a concentration of 400 mM in a solution of 50 mM HEPES buffer, 50 mM NaCl, 0.05% Tween-80, pH 8.0.
  • Stock solution of NEP 24.11 was prepared at a concentration of 100 pg/mL in water. Stability of oligomers to NEP 24.11 was assessed by conducting protease reaction in a 96- well plates at 20 °C.
  • Enzymatic degradation (Pancreatin).
  • Stock solutions of the oligomers were prepared at a concentration of 250 mM in DMSO.
  • Stock solution of pancreatin was prepared at a concentration of 10 mg/mL in water.
  • 2 pL of pancreatin stock solution was diluted 1/500 with a solution of TRIS 10 mM pH 7.5 to afford a final concentration of 0.02 mg/mL.
  • the oligomer was then diluted 1/24 with a solution of TRIS 10 mM pH 7.5 to afford a final concentration of 10 pM and incubated at 37 °C.
  • the frozen sample were defrost, stirred with a vortex 5 min and finally centrifuged 5 min at 16°C.
  • the supernatant was analyzed by LC-MS.
  • the time course of oligomer degradation was determined by integrating the area of the peak in the extracted ion chromatogram.
  • mice were housed in ventilated and enriched housing cages (310 x 125 x 127 mm 3 ) throughout the experimental phase (PD studies: performed by Physiogenex S.A.S; PK study: performed by TechMed ILL (CNRS)). The mice were housed in groups of 3 animals during the study, on a normal 12 hours light cycle (at 8:00 pm lights off), 22 ⁇ 2 °C and 50 ⁇ 10 % relative humidity. A standard chow diet (RM1 (E) 801492, SDS) and tap water were provided ad libitum. All procedures were performed in accordance with the Guide for the Care and Use of Laboratory Animals (revised 1996 and 2011, 2010/63/EU) and French laws.
  • PD studies performed by Physiogenex S.A.S
  • PK study performed by TechMed ILL (CNRS)
  • the mice were housed in groups of 3 animals during the study, on a normal 12 hours light cycle (at 8:00 pm lights off), 22 ⁇ 2 °C and 50 ⁇ 10 %
  • mice Male C57BL/6J mice (Charles River laboratories) (8 weeks old, 20-25g)
  • mice Male C57BL/6J mice (Charles River laboratories) (8 weeks old, 20-25g)
  • i.v. route 5 pg / mouse i.v. (200 pg/kg, 50 nmol/kg)
  • test items 200 pg/kg, 50 nmol/kg
  • mice Fifteen mice (C57B16) were treated with GLP-1 analogues via i.v. injections (1 mg/kg) formulated at 2 mg/mL in PBS IX. After 15 min, lh, 2h and 4h, mice were sacrificed and blood sample were collected. The plasma was separated by centrifugation and the samples were frozen at -80°C before analysis. A volume of 400 pL of each sample of plasma was mixed with 1 ml of acetonitrile to precipitate the protein and extract the compound. The sample were then vortexed and centrifuged (15 000 g-force, 5 min, 16 °C) to sediment the precipitated protein. The supernatant was analysed by LC-MS/MS using a UHPLC coupled to LC-MS 8030 Shimadzu triple quadrupole.
  • Azido building block for oligourea part synthesis on solid support [00277] Azido building block for oligourea part synthesis on solid support. [00278] The building blocks containing Ala-, Glu- Tyr- and lie-type side chains were synthesized as previously reported. 1 ⁇ 2
  • a iBuOCOCI, NMM, THF, -10°C
  • b NaBH 4 , THF, H 2 0, 0°C
  • d NaN 3 , DMF, 80°C;
  • a iBuOCOCI, NMM, THF, -10°C
  • b NaBH 4 , THF, H 2 0, 0°C
  • c PPh 3 , Imidazole, l 2 , DCM
  • d NaN 3 , DMF;
  • Oligomers 2-24 were synthesized using the following general procedure. Sieber resin ( ⁇ 160 mg, loading 0.62 mmol/g) was swelled in DMF (3 mL) for 30 min. All steps were performed under microwave irradiation. The synthesis were conducted with microwave irradiation using the Liberty BlueTM microwave peptide synthesizer from CEM.
  • Al Fmoc deprotection.
  • the A-Fmoc protecting group was removed with 20% piperidine in DMF (3 mL) with the standard liberty blue methods. 3
  • A2 Coupling of Fmoc-amino acid.
  • A-Fmoc- a amino acid (5 equiv relative to the resin loading) were coupled with PyBOP (5 equiv relative to the resin loading) and DIEA (10 equiv relative to the resin loading) as coupling reagent using the standard liberty blue methods.
  • PyBOP 5 equiv relative to the resin loading
  • DIEA 10 equiv relative to the resin loading
  • A3 Coupling of activated N3-building bloc. Each activated monomer (3 equiv relative to the resin loading) was coupled twice using DIEA (10 equiv relative to the resin loading) under microwave irradiation (70°C, 50W, 20 min) in DMF (4 mL).
  • A4 Reduction of azide group. The reduction of the azido group was performed twice in a mixture of l,4-dioxane/H 2 0 (7:3 v/v) (5 mL) with a 1M PMe 3 solution in THF (10 equiv relative to the resin loading) under microwave irradiation (50°C, 50W, 30 min).
  • A5 Cleavage from the resin. After completion of the synthesis, the resin was transferred into a syringe with a frit, and washed three times with DMF, three times with CH2CI2 and three times with Et 2 0. Cleavage from the resin was performed using 95% TFA with 2.5% triisopropylsilane and 2.5% water (3 mL). After 2h the resin was filtered and discarded. Diethyl ether was added to precipitate the oligomer and the solid was triturated and filtrated.
  • A6 Purification and characterization. Analytical RP-HPLC analyses were performed on a Dionex U3000SD using a Macherey-Nagel Nucleodur C18ec column (4 x 100 mm, 3 pm) at a flow rate of 1 mL/min with UV detection at 200 nm. The mobile phase was composed of 0.1% (v/v) TFA-H2O (Solvent A) and 0.1% (v/v) TFA-CH3CN (solvent B).
  • LC-MS analyses were carried out on a UHPLC (Agilent 1290 Infinity) coupled to a ESI -MS Tof (Agilent 6230 ESI).
  • Electrospray ionization mass spectrometry (ESI-MS) experiments were performed on an Agilent 6560 DTIMS-Q-TOF spectrometer (Agilent Technologies, Santa Clara, CA), with the dual-ESI source operated in positive ion mode.
  • the oligomer was synthesized using procedure A. Then the resin was transferred in a 10 mL syringe, 5 mL of DCM was added and the Alloc group was removed using Pd(Ph3)4 (30 mg, 0.25 equiv relative to the resin loading) and phenylsilane (135 pL, 1.1 equiv relative to the resin loading) at room temperature for 45 min.
  • the resin was washed with DMF (2x) and DCM (3x), then DCM (5 mL), Fmoc-OcCh-OH (193 mg, 5 equiv relative to the resin loading), PyBop (260 mg, 5 equiv relative to the resin loading) and DIEA (93 pL, 5 equiv relative to the resin loading) were loaded on the resin and it was shaken for 2 hours at room temperature and again Fmoc group was removed with piperidine (20%) twice.
  • the resin was washed with DMF (2x) and DCM (3x), then DCM (5 mL), V-Fmoc-Glu(OH)-0/Bu (222 mg, 5 equiv relative to the resin loading), PyBop (260 mg, 5 equiv relative to the resin loading), and DIEA (93 pL, 5 equiv relative to the resin loading) were loaded on the resin and it was shaken for 2 hours at room temperature. Fmoc group was removed with piperidine in DMF (20%), 2 times 20 min.
  • the resin was washed with DMF (2x) and DCM (3x), then the 18-(ter- butoxy)18-oxooctadecanoic acid (111 mg, 3 equiv relative to the resin loading), ByBop (156 mg, 3 equiv relative to the resin loading) and DIEA (52 pL, 3 equiv relative to the resin loading) were loaded on the resin and it was shaken for 2 hours at room temperature.
  • V-Fmoc-Lys(Boc)-OH at position 20 was replaced by V-Fmoc-Lys(Alloc)-OH and V-Fmoc-His(Trt)-OH at position 1 was replaced by V-Boc-His(Boc)-OH.
  • V-Fmoc-Gly-OH was coupled on the resin with mixt anhydride (novabiochem procedure 4 ).
  • V-Fmoc-Gly-OH 300 mg, 5 equiv relative to the resin loading
  • dry DCM 3 mL
  • A'-Dicyclohexylcarbodiimide 103 mg, 2.5 equiv relative to the resin loading
  • DCM dimethylaminopyridine
  • Peptide 1 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 1 was purified by semi-preparative HPLC. 6.1 mg was obtained (yield 1.8 %).
  • HPLC: R t 5.29 mm (10-100%; CH3CN 0.1 % TFA in H 0 0.1% TFA, 10 mm, C18); LC-MS (m/z 3340.71): 668.78 [M+5H] 5+ , 835.75 [M+4H] 4+ , 1114.36 [MT3H] 3+ 1671.10 [M+2H] 2+ .
  • Figure 7 A demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide 1 in cells expressing the GLP-1R.
  • Figure 7B demonstrates the enzymatic degradation of peptide 2 by NEP 24.11.
  • Figure 7C demonstrates the mouse plasma degradation results for peptide 2.
  • Peptide-oligourea hybrid 2 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 2 was purified by semi-preparative HPFC. 10.13 mg was obtained (yield 3.1 %).
  • HPLC: R t 5.28 mm (10-100% CH3CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); LC-MS (m/z 3296.70): 660.15 [M+5H] 5+ , 825.19[M+4H] 4+ , 1099.58 [M+3H] 3+ , 1649.37 [M+2H] 2+ .
  • Figure 8 A demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 2 in cells expressing the GFP-1R.
  • Figure 8B demonstrates the enzymatic degradation of peptide 2 by NEP 24.11.
  • Figure 8C demonstrates the mouse plasma degradation results for peptide-oligourea 3.
  • H-HGEGTFTSD A U A U A U FEGQAAKEFIAWFVKGRG-NH 2 (SEQ ID NO. 3)
  • Peptide-oligourea hybrid 4 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 3 was purified by semi-preparative HPFC. 28.4 mg was obtained (yield 8.9 %).
  • HPFC: R t 5.25 mm (10-100% CH3CN 0.1 % TFA in H2O 0.1% TFA, 10 min, C18); ESI+ (m/z 3204.61): 641.67 [M+5H] 5+ , 802.13 [M+4H] 4+ ,
  • Figure 9 demonstrattes the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea 3 in cells expressing the GLP-1R.
  • Peptide-oligourea hybrid 4 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 4 was purified by semi-preparative HPLC. 7.0 mg was obtained (yield 2.2 %).
  • HPLC: R t 5.01 mm (10-100% CH3CN 0.1 % TFA in H2O 0.1% TFA, 10 mm, C18); ESI+ (m/z 3190.58): 639.13 [M+5H] 5+ , 798.60 [M+4H] 4+ , 1064.47 [M+3H] 3+ , 1595.87 [M+2H] 2+ .
  • Figure 10 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea 4 in cells expressing the GLP-1R.
  • Peptide-oligourea hybrid 5 was synthesized using the general procedure A starting from Sieber resin (160 mg, 0.1 mmol). The final product 5 was purified by semi-preparative HPLC. 2.4 mg was obtained (yield 0.8 %).
  • HPLC: R t 5.08 mm (10-100% CH3CN 0.1 % TFA in H2O 0.1% TFA, 10 mm, C18); LC-MS (m/z 3282.67): 657.36[M+5H] S+ , 821.45 [M+4H] 4+ , 1094.93 [M+3H] 3+ , 1641.89 [M+2H] 2+ .
  • Figure 11 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea 5 in cells expressing the GLP-1R ( Figure 11 A).
  • Figure 11B demonstrate the enzymatic degradation of peptide-oligourea hybrid 6 by NEP 24.11.
  • Figure 11C demonstrates the mouse plasma degradation of peptide-oligourea hybrid 5.
  • Peptide-oligourea hybrid 6 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 6 was purified by semi-preparative HPLC. 9.3 mg was obtained (yield 2.95 %).
  • HPLC: R t 5.08 mm (10-100% CH3CN 0.1 % TFA in H2O 0.1% TFA, 10 mm, C18); ESI+ (m/z 3148.54): 630.67 [M+5H] 5+ , 788.00 [M+4H] 4+ ,
  • Figure 12 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea 6 in cells expressing the GLP-IR.
  • Peptide-oligourea hybrid 7 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 7 was purified by semi-preparative HPLC. 11.88 mg was obtained (yield 3.7 %).
  • HPLC: 3 ⁇ 4 5.13 mm (10-100% CH 3 CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); ESI+ (m/z 3178.57): 795.51 [M+4H] 4+ , 1060.63 [M+3H] 3+ , 1590.80 [M+2H] 2+
  • Figure 13 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 7 in cells expressing the GFP-1R.
  • Peptide-oligourea hybrid 8 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 8 was purified by semi-preparative HPFC. 3.22mg was obtained (yield 1.0 %).
  • HPFC: R t 5.20 mm (10-100% CH 3 CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); ESI+ (m/z 3213.61): 643.60 [M+5H] 5+ , 804.33 [M+4H] 4+ , 1072.07 [M+3H] 3+ , 1607.73 [M+2H] 2+ .
  • Figure 14 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 8 in cells expressing the GFP-1R.
  • Peptide-oligourea hybrid 9 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 9 was purified by semi-preparative HPLC. 2.3 mg was obtained (yield 0.7 %).
  • HPLC: R t 5.11 mm (10-100% CH 3 CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); LC-MS (m/z 3363.74): 673.74 [M+5H] 5+ , 841.68 [M+4H] 4+ , 1121.90 [M+3H] 3+ , 1682.85 [M+2H] 2+ .
  • Figure 15 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea 9 in cells expressing the GLP-1R ( Figure 15A).
  • Figure 15B demonstrate the enzymatic degradation of peptide-oligourea hybrid 9 by NEP 24.11.
  • Figure 15C demonstrates the mouse plasma degradation of peptide-oligourea hybrid 9.
  • Figure 16 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 10 in cells expressing the GLP-1R.
  • Peptide-oligourea 11 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 11 was purified by semi-preparative HPLC. 17.6 mg was obtained (yield 5.3 %).
  • HPLC: R t 5.27 mm (10-100% CH 3 CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); LC-MS (m/z 3313.73): 663.55 [M+5H] 5+ , 829.19 [M+4H] 4+ , 1105.25 [MT3H] 3+ .
  • Figure 17 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 11 in cells expressing the GLP-1R ( Figure 17A).
  • Figure 17B demonstrates the enzymatic degradation of peptide-oligourea hybrid 11 by NEP 24.11.
  • Figure 17C demonrates the mouse plasma degradation of peptide- oligourea hybrid 11.
  • Peptide-oligourea hybrid 12 has been synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 12 was purified by semi preparative HPLC. 10.2 mg was obtained (yield 3.1 %).
  • HPLC: R t 5.19 min (10-100% CH3CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); ESI+ (m/z 3313.73): 829.53 [M+4H] 4+ , 1105.40 [M+3H] 3+ , 1657.87[M+2H] 2+ .
  • Figure 18 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 12 in cells expressing the GLP-1R.
  • Peptide-oligourea hybrid 13 has been synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 13 was purified by semi- preparative HPLC. 10.98 mg was obtained (yield 3.4 %).
  • HPLC: R t 5.45 min (10-100% CH3CN 0.1 % TFA in H2O 0.1% TFA, 10 mm, C18); ESI+ (m/z 3242.61): 811.53 [M+4H] 4+ , 1081.73 [M+3H] 3+ , 1621.87 [M+2H] 2+ .
  • Figure 19 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 13 in cells expressing the GLP-1R.
  • Peptide-oligourea hybrid 14 has been synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 14 was purified by semi preparative HPLC. 6.0 mg was obtained (yield 1.85 %).
  • HPLC: R t 5.48 min (10-100% CH3CN 0.1 % TFA in H2O 0.1% TFA, 10 mm, C18); LC-MS (m/z 3241.62): 649.14 [M+5H] 5+ , 811.17[M+4H] 4+ , 1081.23 [M+3H] 3+ , 1621.33[M+2H] 2+ .
  • Figure 20 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 14 in cells expressing the GLP-1R ( Figure 20A).
  • Figure 20B demonstrates the enzymatic degradation of peptide-oligourea 14 by NEP 24.11.
  • Figure 20C demonstrates the mouse plasma degradation of peptide-oligourea hybrid 14.
  • Peptide-oligourea hybrid 15 has been synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 15 was purified by semi preparative HPLC. 8.4 mg was obtained (yield 2.6 %).
  • HPLC: R t 5.05 min (10-100% CH3CN 0.1 % TFA in H2O 0.1% TFA, 10 mm, C18); ESI+ (m/z 3165.52): 792.27 [M+4H] 4+ , 1056.00 [M+3H] 3+ , 1583.53 [M+2H] 2+ .
  • Figure 21 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 15 in cells expressing the GLP-1R.
  • Figure 22 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea 16 in cells expressing the GLP- 1R ( Figure 22A).
  • Figure 22B demonstrates the enzymatic degradation of peptide-oligourea hybrid 16 by NEP 24.11.
  • Figure 22C demonsrates the mouse plasma degradation of peptide- oligourea 16.
  • Peptide-oligourea hybrid 17 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 17 was purified by semi preparative HPLC. 10.3 mg was obtained (yield 3.3 %).
  • HPLC: R t 4.52 min (10-100% CH3CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); ESI+ (m/z 3157.46): 632.47 [M+5H] 5+ , 790.20 [MT4H] 4+ , 1053.27 [M+3H] 3+ , 1579.73 [M+2H] 2+ .
  • Figure 23 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 17 in cells expressing the GLP-1R.
  • Peptide-oligourea hybrid 18 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 18 was purified by semi preparative HPLC. 10.0 mg was obtained (yield 3.2 %).
  • HPLC: R t 4.60 min (10-100% CH3CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); ESI+ (m/z 3171.48): 635.07 [M+5H] 5+ , 794.00 [MT4H] 4+ , 1058.20 [M+3H] 3+ , 1586.73 [M+2H] 2+ .
  • Figure 24 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 18 in cells expressing the GLP-1R.
  • Peptide-oligourea hybrid Oligomer 19 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 19 was purified by semi-preparative HPLC. 2.3 mg was obtained (yield 0.7 %).
  • HPLC: R t 4.68 min (10-100% CH3CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); LC-MS (m/z 3114.39): 623.72 [M+5H] 5+ , 779.39 [M+4H] 4+ , 1038.86 [M+3H] 3+ , 1557.78 [M+2H] 2+ .
  • Figure 25 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 19 in cells expressing the GLP-1R.
  • Peptide-oligourea hybrid 20 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 20 was purified by semi preparative HPLC. 2.05 mg was obtained (yield 0.6 %).
  • HPLC: R t 5.21 min (10-100% CH3CN 0.1 % TFA in H2O 0.1% TFA, 10 mm, C18); LC-MS (m/z 3243.55): 649.59 [M+5H] 5+ , 811.73 [M+4H] 4+ , 1081.95 [M+3H] 3+ , 1622.41 [M+2H] 2+ .
  • Figure 26 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination peptide-oligourea hybrid 20 in cells expressing the GLP-1R.
  • Peptide-oligourea hybrid 21 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 21 was purified by semi preparative HPLC. 2.7 mg was obtained (yield 0.8 %).
  • HPLC: R t 5.81 min (10-100% CH3CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); LC-MS (m/z 3200.52): 800.97 [M+4H] 4+ , 1067.95 [M+3H] 3+ , 1600.89 [M+2H] 2+ .
  • Figure 27 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 21 in cells expressing the GLP-1R.
  • Peptide-oligourea hybrid 22 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 22 was purified by semi preparative HPLC. 2.2 mg was obtained (yield 0.7 %).
  • HPLC: R f 6.45 min (10-100% CH3CN 0.1 % TFA in H 2 0 0.1% TFA, 10 mm, C18); LC-MS (m/z 3242.60): 649.59 [M+5H] 5+ , 811.48 [M+4H] 4+ , 1081.63 [M+3H] 3+ , 1621.91 [M+2H] 2+ .
  • Figure 28 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea 22 in cells expressing the GLP- 1R ( Figure 28A).
  • Figure 28B demonstrates the enzymatic degradation of peptide-oligourea hybrid 22 by NEP 24.11.
  • Figure 28C demonstrates the muse plasma degradation of peptide- oligourea hybrid 22.
  • Peptide-oligourea hybrid 23 was synthesized using the general procedure A starting from sieber resin (160 mg, 0.1 mmol). The final product 23 was purified by semi preparative HPLC. 5.5 mg was obtained (yield 1.7 %).
  • HPLC: R t 5.57 min (10-100% CH3CN 0.1 % TFA in H2O 0.1% TFA, 10 mm, C18); LC-MS (m/z 3264.66): 653.69 [M+5H] 5+ , 816.87 [M+4H] 4+ , 1088.84 [M+3H] 3+ .
  • Figure 29 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 23 in cells expressing the GLP-1R ( Figure 29 A).
  • Figure 29B demonstrates the enzymatic degradation of peptide-oligourea hybrid 23 by NEP 24.11.
  • Figure 29C demonstrates the mouse plasma degradation of peptide- oligourea hybrid 24.
  • Figure 30 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide-oligourea hybrid 24 in cells expressing the GLP-1R (Figure 30A).
  • Figure 30B demonstrates the enzymatic degradation of peptide-oligourea hybrid 24 by Pancreatin.
  • Figure 30C demonstrates the mouse plasma degradation of peptide- oligourea hybrid 24.
  • H-HAibEGTFTSD V S S YLEGQ AAK(2xOEG-yE-C 18 diacid)EFIAWLVRGRG-
  • Peptide 25 was synthesized using the general procedure C starting from wang resin (220 mg, 0.1 mmol). The final product 25 was purified by semi-preparative HPLC. 2.2 mg was obtained (yield 0.5 %).
  • HPLC: R t 6.13 mm (10-100% CH 3 CN 0.1 % TFA in H 0 0.1% TFA, 10 mm, C18); LC-MS (m/z 4113.60): 823.76 [M+5H] 5+ , 1029.44 [M+4H] 4+ , 1372.22 [MT3H] 3+ .
  • Figure 31 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of peptide 26 in cells expressing the GLP-1R ( Figure 31 A).
  • Figure 3 IB demonstrate the enzymatic degradation of peptide 25 by Pancreatin.
  • Figure 31C demonstrates the mouse plasma degradation of peptide 25.
  • Figure 32 demonstrates the enzymatic degradation by NEP 24.11 of the respective peptides (SEQ ID Nos. 1, 2, 5, 9, 11, 14, 16, 22, and 23). (two-way anova and Bonferroni post test: *p ⁇ 0.05; ** p ⁇ 0,01; *** p ⁇ 0,001).
  • Figure 33 demonstrates the mouse plasma degradation of the respective peptides (SEQ ID Nos.1, 2, 5, 9, 11, 14, 16, 22, and 23).
  • Figure 34 demonstrates the mouse plasma degradation assay (two-way anova and Bonferroni post test: *p ⁇ 0.05; ** p ⁇ 0,01; *** p ⁇ 0,001) (A); (B) Half life in pancreatin (two-way
  • Figure 35 demonstrates the enzymatic degradation (Pancreatin) (two-way anova and Bonferroni post test: *p ⁇ 0.05; ** p ⁇ 0,01; *** p ⁇ 0,001) (A); (B) Half life in pancreatin (two- way anova and Dunnett post test: *p ⁇ 0.05; ** p ⁇ 0,01; *** p ⁇ 0,001); (C) EC50 values and standard error of the mean values.
  • IPGTT 2 h after dosing Blood glucose measurements before the IPGTT
  • Figure 36 demonstrates the fasting blood glucose (mg/dL) before and after i.v treatment in mice treated with vehicle, 1, 14, 22, 23, 5 pg/mouse (two-way ANOVA and Bonferroni post-test: ** p ⁇ 0,01 ; *** p ⁇ 0,001).
  • cAMP concentration was determined by dividing the signal measured at 665 nm by that measured at 620 nm (ratio). The results are expressed as a percent of the control response to 10 nM Forskolin.
  • the standard reference agonist is GFP-1-G 2 -NH 2 , which is tested in each experiment at several concentrations to generate a concentration-response curve from which its EC50 value and SEM is calculated using GraphPad Prism.
  • Figure 37 demonstrates the concentration-response curve (receptor-mediated cAMP produced) for EC50 determination of oligomer 24 and 25 in cells expressing the GLP-1R (A).
  • B EC50 values and standard error of the mean values.
  • peptide-oligourea chimeric foldamers compounds having a polypeptide portion contiguous with or linked to oligomers of amino acids having an N, N’ -linked urea bridging unit
  • Oligoureas can be derived from building blocks with any desired amino acid side chain.
  • the chimeric compounds as described herein demonstrate regular and persistant helical conformations and improved helix stability.
  • chimeric foldamers as described herein can adopt desired secondary structures similar to native peptides, including, e.g., linear, cyclic or helicoidal structures, they can serve as, for example, receptor ligands, effector molecules, agonists, antagonists, modulators of protein-protein interactions, organocatalysts or enzymes.
  • Compound 25 (SEQ ID NO: 25) - HAibEGTFTSDVSSYLEGQAAK(2xOEG-YE-C18 diacid)EFIAWLVRGRG-OH (semaglutide)

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Abstract

La présente description concerne des foldamères peptidomimétiques et leur synthèse. En particulier, l'invention concerne des foldamères peptidomimétiques hybrides peptidiques-amino-urée comprenant une partie de peptide d'acide aminé alpha et une partie d'oligourée.
PCT/EP2020/050880 2019-01-18 2020-01-15 Composés hybrides de peptide-oligourée WO2020148317A1 (fr)

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WO2015024955A1 (fr) * 2013-08-21 2015-02-26 Ureka Sarl Composés chimériques de peptide-oligourée et leurs procédés d'utilisation
US20170298112A1 (en) * 2016-04-19 2017-10-19 Ureka Sarl Peptide-oligourea foldamer compounds and methods of their use

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